In Silico Biology 5, 0046 (2005); ©2005, Bioinformation Systems e.V.  


T cell receptor/peptide/MHC molecular characterization and standardized pMHC contact sites in IMGT/3Dstructure-DB


Quentin Kaas and Marie-Paule Lefranc*




IMGT, the international ImMunoGeneTics information system®
Université Montpellier II, Laboratoire d'ImmunoGénétique Moléculaire LIGM
UPR CNRS 1142, Institut de Génétique Humaine IGH
141 rue de la Cardonille
34396 Montpellier Cedex 5, France
Phone: +33-4-99 61 99 65, Fax: +33-4-99 61 99 01



*Corresponding author
   Email: lefranc@ligm.igh.cnrs.fr
   Institut Universitaire de France





Edited by E. Wingender; received September 02, 2005; revised and accepted September 18, 2005; published October 20, 2005



Abstract

One of the key elements in the adaptive immune response is the presentation of peptides by the major histocompatibility complex (MHC) to the T cell receptors (TR) at the surface of T cells. The characterization of the TR/peptide/MHC trimolecular complexes (TR/pMHC) is crucial to the fields of immunology, vaccination and immunotherapy. In order to facilitate data comparison and cross-referencing between experiments from different laboratories whatever the receptor, the chain type, the domain, or the species, IMGT, the international ImMunoGeneTics information system® (http://imgt.cines.fr), has developed IMGT-ONTOLOGY, the first ontology in immunogenetics and immunoinformatics. In IMGT/3Dstructure-DB, the IMGT three-dimensional structure database, TR/pMHC molecular characterization and pMHC contact analysis are made according to the IMGT Scientific chart rules, based on the IMGT-ONTOLOGY concepts. IMGT/3Dstructure-DB provides the standardized IMGT gene and allele names (CLASSIFICATION), the standardized IMGT labels (DESCRIPTION) and the IMGT unique numbering (NUMEROTATION). As the IMGT structural unit is the domain, amino acids at conserved positions always have the same number in the IMGT databases, tools and Web resources. For the TR alpha and beta chains, the amino acids in contact with the peptide/MHC (pMHC) are defined according to the IMGT unique numbering for V-DOMAIN. The MHC cleft that binds the peptide is formed by two groove domains (G-DOMAIN), each one comprising four antiparallel beta strands and one alpha helix. The IMGT unique numbering for G-DOMAIN applies both to the first two domains (G-ALPHA1 and G-ALPHA2) of the MHC class I alpha chain, and to the first domain (G-ALPHA and G-BETA) of the two MHC class II chains, alpha and beta. Based on the IMGT unique numbering, we defined eleven contact sites for the analysis of the pMHC contacts. The TR/pMHC contact description, based on the IMGT numbering, can be queried in the IMGT/StucturalQuery tool, at http://imgt.cines.fr.

Availability: IMGT/3Dstructure-DB is freely available at http://imgt.cines.fr.

Keywords: IMGT, T cell receptor, TR, major histocompatibility complex, MHC, pMHC, TR/peptide/MHC complex, TR/pMHC, three-dimensional structure, 3D structure, contact analysis, IMGT/3Dstructure-DB, IMGT/StructuralQuery, immunoinformatics, immunogenetics, immune system



Introduction

T cells are involved in the specific immune response against a stress of viral, bacterial, fungal or tumoral origin. They identify antigenic peptides presented by the major histocompatibility complex (MHC) cell surface glycoproteins. The recognition is carried out by the T cell receptor complex (TcR), a multisubunit transmembrane surface complex made up of a T cell receptor (TR) and of the CD3 chains, that is associated, in the immunological synapse, to the CD4 or CD8 coreceptors, to the CD28 and CTLA-4 costimulatory proteins, to the CD2 adhesion molecule and to intracellular kinases [1]. The TR directly binds the peptide/MHC complex (pMHC), and activates the T cell through interactions with the CD3 and other components of the TcR [2, 3, 4]. Three-dimensional (3D) structures of the TR, pMHC and TR/pMHC complexes provide an atomic description of their interactions [5, 6].

Since 1989, IMGT, the international ImMunoGeneTics information system® [7, 8, 9, 10], http://imgt.cines.fr, created by Marie-Paule Lefranc, Laboratoire d'ImmunoGénétique Moléculaire (LIGM) (Université Montpellier II and CNRS) at Montpellier, France, has offered standardized genetic and structural data on immunoglobulins (IG), TR and MHC, and on related proteins of the immune system (RPI) that belong to the immunoglobulin superfamily (IgSF) and to the MHC superfamily (MhcSF). In order to facilitate data comparison and cross-referencing between experiments from different laboratories whatever the receptor, the chain type, the domain, or the species, IMGT developed IMGT-ONTOLOGY [11], the first ontology in immunogenetics and immunoinformatics.

Based on the IMGT-ONTOLOGY concepts, the IMGT Scientific chart provides the controlled vocabulary and the annotation rules necessary for the identification, the description, the classification and the numbering of the IG, TR, MHC and RPI [8]. The IDENTIFICATION concept refers to the IMGT standardized keywords indispensable for the sequence and 3D structure assignments. The DESCRIPTION concept provides the IMGT standardized labels used to describe structural and functional regions that compose IG, TR, MHC and RPI sequences and 3D structures. Standardized labels have also been defined to characterize the three-dimensional assembly of domains and chains. The CLASSIFICATION concept provides immunologists and geneticists with a standardized nomenclature per locus and per species. The human IG and TR gene nomenclature elaborated by IMGT was approved by the Human Genome Organisation (HUGO) Nomenclature Committee, HGNC [12], in 1999. The mouse IG and TR gene names with IMGT reference sequences were provided by IMGT to HGNC and to the Mouse Genome Database (MGD) [13], in July 2002. The NUMEROTATION concept provides the IMGT unique numbering for the IG and TR V-DOMAIN and V-LIKE-DOMAIN of the IgSF proteins other than IG or TR [14],and for the IG and TR C-DOMAIN and C-LIKE-DOMAIN of the IgSF proteins other than IG or TR [15]. An IMGT unique numbering has also been set up for the MHC G-DOMAIN and G-LIKE-DOMAIN of the MhcSF proteins other than MHC [16].

The IMGT standardization has allowed to build a unique frame for the comparison of the TR, peptides and MHC interactions in the different resources provided by the information system. IMGT/3Dstructure-DB [5], the IMGT structural database, is used with the IMGT sequence databases (IMGT/LIGM-DB [7, 8] and IMGT/MHC-DB [17]), the IMGT gene database (IMGT/GENE-DB [18]), the IMGT tools for sequence analysis (IMGT/V-QUEST [19], IMGT/JunctionAnalysis [20]) and the IMGT tool for 3D structure analysis (IMGT/StructuralQuery [5]), to explore the TR and MHC conserved structural features. In this paper, we describe the molecular characterization and standardized contact analysis of the TR/pMHC complexes in IMGT/3Dstructure-DB. Coordinate files are from IMGT/3Dstructure-DB [5], http://imgt.cines.fr, with original crystallographic data from the Protein Data Bank PDB [6]. Eleven IMGT pMHC contact sites were defined (C1 to C11) which can be used to compare pMHC interactions. We provide the description of the interactions of the TR V-ALPHA and TR V-BETA with MHC and the peptide using the IMGT unique numbering for V-DOMAIN [14] and the IMGT unique numbering for G-DOMAIN [16], which allows, for the first time, to compare interaction data, whatever the TR gene group (TRAV, TRBV), whatever the MHC class (MHC-I, MHC-II), and whatever the species (Homo sapiens, Mus musculus).



TR and MHC chains and domains

The T cell receptor (TR) is made of two chains, an alpha chain (TR-ALPHA) and a beta chain (TR-BETA) for the TR-ALPHA_BETA receptor, a gamma chain (TR-GAMMA) and a delta chain (TR-DELTA) for the TR-GAMMA_DELTA receptor [1]. Each complete TR chain comprises an extracellular region made up of a variable domain V-DOMAIN (for instance, V-ALPHA for the alpha chain) and a constant domain C-DOMAIN (for instance, C-ALPHA for the alpha chain), a connecting region, a transmembrane region and a very short intracytoplasmic region (Table 1, Figure 1).

Table 1: IMGT standardized labels for the DESCRIPTION of the T cell receptors, chains, domains and regions.
IMGT receptor labelsIMGT chain labelsIMGT domain labelsIMGT region labels
TR-ALPHA_BETATR-ALPHA V-ALPHAV-J-REGION
C-ALPHAPart of C-REGION (1)
TR-BETA V-BETAV-D-J-REGION
C-BETAPart of C-REGION (1)
TR-GAMMA_DELTATR-GAMMA V-GAMMAV-J-REGION
C-GAMMAPart of C-REGION (1)
TR-DELTAV-DELTAV-D-J-REGION
C-DELTAPart of C-REGION (1)
(1) The TR chain C-REGION also includes the CONNECTING-REGION, the TRANSMEMBRANE-REGION and the CYTOPLASMIC-REGION which are not present in the 3D structures (Correspondence between labels for IG and TR domains in IMGT/3Dstructure-DB and IMGT/LIGM-DB, IMGT Scientific chart).

The MHC-I is formed by the association of an heavy chain (I-ALPHA) and a light chain (beta-2-microglobulin B2M) (Table 2, Figure 1). The MHC-II is an heterodimer formed by the association of an alpha chain (II-ALPHA) and a beta chain (II-BETA). The I-ALPHA chain of the MHC-I, and the II-ALPHA and II-BETA chains of the MHC-II comprise an extracellular region made of three domains for the MHC-I and of two domains for the MHC-II chains, a connecting region, a transmembrane region and an intracytoplasmic region.



Figure 1: T cell receptor/peptide/MHC complexes with MHC class I (TR/pMHC-I) and MHC class II (TR/pMHC-II). [D1], [D2] and [D3] indicate the domains. (A) 3D structures of TR/pMHC-I (1oga) [22] and TR/pMHC-II (1j8h) [23]. The figure was generated with Pymol, http://pymol.sourceforge.net. (B) Schematic representation of TR/pMHC-I and TR/pMHC-II. The TR (TR-ALPHA and TR-BETA chains), the MHC-I (I-ALPHA and beta-2-microglobulin B2M chains) and the MHC-II (II-ALPHA and II-BETA chains) are shown with the extracellular domains (V-ALPHA and C-ALPHA for the TR-ALPHA chain; V-BETA and C-BETA for the TR-BETA chain; G-ALPHA1, G-ALPHA2 and C-LIKE for the I-ALPHA chain; C-LIKE for B2M; G-ALPHA and C-LIKE for the II-ALPHA chain; II-BETA and C-LIKE for the II-BETA chain), and the connecting, transmembrane and cytoplasmic regions. Arrows indicate the peptide localization in the G-DOMAIN groove. The MHC G-DOMAINs and TR V-DOMAINs are likely to be in a diagonal rather than in a vertical position relative to the cell surface [24, 25].


The I-ALPHA chain comprises two groove domains (G-DOMAIN), G-ALPHA1 [D1] and G-ALPHA2 [D2], and one C-LIKE domain [D3]. The B2M corresponds to a single C-LIKE domain. The II-ALPHA chain and the II-BETA chain each comprises two domains, G-ALPHA [D1] and C-LIKE [D2], and G-BETA [D1] and C-LIKE [D2] (Table 2). Only the extracellular region that corresponds to these domains has been crystallized (Figure 1).

Table 2: IMGT standardized labels for the DESCRIPTION of the MHC receptors, chains, domains and domain numbers.
IMGT receptor labelsIMGT chain labelsIMGT domain labelsDomain numbers
MHC-I-ALPHA_B2MI-ALPHAG-ALPHA1[D1]
G-ALPHA2[D2]
C-LIKE[D3] (1)
B2MC-LIKE[D]
MHC-II-ALPHA_BETAII-ALPHAG-ALPHA[D1]
C-LIKE[D2] (1)
II-BETAG-BETA[D1]
C-LIKE[D2] (1)
(1) The I-ALPHA, II-ALPHA and II-BETA chains includes at the C-terminal end of the C-LIKE-DOMAIN, the CONNECTING-REGION, the TRANSMEMBRANE-REGION and the CYTOPLASMIC-REGION which are not present in the 3D structures.

The TR V-DOMAINs and MHC G-DOMAINs that are directly involved in the TR/pMHC interactions are described in the next sections.



TR V-DOMAINs

The V-DOMAINs have an immunoglobulin fold, that is an antiparallel beta sheet sandwich structure with 9 strands [14, 21], the A, B, E and D strands being on one sheet, and the G, F, C, C' and C" strands on the other sheet. These strands are indicated in the IMGT Colliers de Perles (Figure 2) which are IMGT 2D graphical representations based on the IMGT unique numbering for V-DOMAINs [14]. IMGT Colliers de Perles of the V-ALPHA and V-BETA domains from 1ao7 [26] are shown as examples in Figure 2.

The V-ALPHA and V-BETA domains share main conserved characteristics of the V-DOMAIN which are the disulfide bridge between cysteine 23 (1st-CYS) and cysteine 104 (2nd-CYS), and the other hydrophobic core residues tryptophan 41 (CONSERVED-TRP) and leucine (or hydrophobic) 89 [14] (Figure 2). The A strand comprises positions 1 to 15, B strand positions 16 to 26, C strand positions 39 to 46, C' strand positions 47 to 55, C" strand positions 66 to 74, D strand positions 75 to 84, E strand positions 85 to 96, F strand positions 97 to 104, and G strand positions 118 to 128 [14]. Compared to the general V-DOMAIN 3D structure, the V-ALPHA domains have shorter C" and D strands at the C’D turn (with 7 gaps at positions 71 to 77) and, in contrast, longer D and E strands at the DE turn (with additional positions at 84A, 84B and 84C).



Figure 2: IMGT Collier de Perles of the V-ALPHA and V-BETA domains from 1ao7 [26] (IMGT/ 3Dstructure-DB, http://imgt.cines.fr) (A) on one layer (B) on two layers. Amino acids are shown in the one-letter abbreviation. Hydrophobic amino acids (hydropathy index with positive value) and tryptophan (W) found at a given position in more than 50% of analyzed IG and TR sequences are shown. The CDR-IMGT are limited by amino acids shown in squares, which belong to the neighbouring FR-IMGT and represent anchor positions. The CDR3-IMGT extend from position 105 to 117 [14]. Hatched circles correspond to missing positions according to the IMGT unique numbering. Arrows indicate the direction of the beta sheets and their different designations in 3D structures.


The three hypervariable loops or complementarity determining regions (CDR-IMGT) of each V-DOMAIN are involved in the pMHC recognition. The CDR1-IMGT comprises positions 27 to 38, the CDR2-IMGT positions 56 to 65 and the CDR3-IMGT positions 105 to 117 [14]. The CDR3-IMGT corresponds to the junction resulting from the V-J and V-D-J rearrangement, and is more variable in sequence and length than the CDR1-IMGT and CDR2-IMGT that are encoded by the V-REGION only [1]. Lengths of the CDR1-IMGT are shown separated by dots between brackets [14]. For examples, 1ao7 [6.5.11] V-ALPHA means that in the V-ALPHA domain of 1ao7, CDR1-IMGT has a length of 6 amino acids, CDR2-IMGT a length of 5 amino acids and CDR3-IMGT a length of 11 amino acids, and 1ao7 [5.6.14] V-BETA means that in the V-BETA domains of 1ao7, CDR1-IMGT, CDR2-IMGT and CDR3-IMGT have a length of 5, 6 and 14 amino acids, respectively [14].



Figure 3: IMGT Collier de Perles of MHC G-DOMAINs. (A) MHC-I G-ALPHA1 and G-ALPHA2 domains (B) MHC-II G-ALPHA and G-BETA domains. MHC-I G-DOMAINs are from 1ao7 [26] and MHC-II G-DOMAINs are from 1j8h [23] (IMGT/3Dstructure-DB [5], http://imgt.cines.fr). Amino acid positions are according to the IMGT unique numbering for G-DOMAIN [16]. Positions 61A, 61B and 72A are characteristic of the G-ALPHA2 and G-BETA domains (and are not reported in the G-ALPHA1 and G-ALPHA IMGT Collier de Perles).



pMHC contact analysis

Owing to its standardization, the IMGT unique numbering for G-DOMAIN [16] has allowed to graphically represent, in the IMGT Colliers de Perles for G-DOMAIN, the MHC amino acid positions that have contacts with the peptide side chains. Eleven IMGT pMHC contact sites were defined (C1 to C11) which can be used to compare pMHC interactions. Examples of contact sites for a MHC-I binding a 8-amino acid peptide (1jtr), for a MHC-I binding a 9-amino acid peptide (1ao7) and for a MHC-II binding 9 amino acids of the peptide in the groove (1j8h) are shown in Figures 4, 5 and 6, respectively.

In contrast to previous attempts to define pockets [28], structural data for defining the IMGT pMHC contact sites take into account the length of the peptides and are considered independently of the MHC class and sequence polymorphisms. The interactions between the peptide amino acid side chains and MHC amino acids were computed using an interaction scoring scheme based on true mean energy ratio. The score assigned to each contact is a constant value, independent on the distance between atoms (hydrogen bond 40, water mediated hydrogen bond 20, contact between polar atoms 20, contact between non polar atoms 1). All direct contacts (defined with a cut off equal to the sum of the atom van der Waals radii and of the diameter of a water molecule) and water mediated hydrogen bonds were taken into account for the definition of the IMGT pMHC contact sites. The analysis was carried out for the pMHC available in IMGT/3Dstructure-DB [5], http://imgt.cines.fr. One hundred fourteen 3D structures with peptides of 8, 9 and 10 amino acids bound to MHC-I and forty-four 3D structures of pMHC-II were identified. The contact analysis was performed for the peptide amino acid side chains of the 9 amino acids located in the groove. Results for MHC-I with 8-amino acid peptides (30 pMHC-I 3D structures), MHC-I with 9-amino acid peptides (74 pMHC-I 3D structures), and MHC-II for the 9 amino acids located in the groove (44 pMHC-II 3D structures) are reported in Table 3 (the results for the ten pMHC-I with 10-amino acid peptides are not shown). These "IMGT reference pMHC contact sites" are also available as IMGT Colliers de Perles. They will be updated as the number of 3D structures increases.

IMGT Colliers de Perles for IMGT pMHC contact sites are provided for each individual pMHC and TR/pMHC entry in IMGT/3Dstructure-DB. They allow to easily identify the amino acid contacts between the MHC and the peptide amino acid side chains and to compare them with the "IMGT reference pMHC contact sites".

Table 3: IMGT reference pMHC contact sites. (A) MHC-I, (B) MHC-II.
(A) MHC-I
8-amino acid peptides
  G-ALPHA1G-ALPHA2
C1159 62 63 6673 77 81
C327 24 459
C4 3 9 24 63 66 67 70
C54  
C6 57 9 22 70 747 9 24 26
C96 59 61A 63 66
C10777 73 76 
C11877 80 81 845 26 33 34 55 59
9-amino acid peptides
  G-ALPHA1G-ALPHA2
C115 59 62 63 6673 77 81
C327 9 22 24 34 45 63 66 67 70 
C4 3 7 9 24 66 67 70
C5465 6666
C6570 73 747 26 66 67
C8666 69 70 73 747 24 62 66
C97 7 24 59 61A 63 66
C10872 73 76 8058
C11 977 80 81 845 26 33 34 55 59
(B) MHC-II
  G-ALPHAG-BETA
C1 126 33 34 47 60 61 6277 80 81 82 84 85
C22 72A 73 76
C337 24 62 63 66 67 69 
C4479 11 22 24 66 67 70 73 74
C55 66
C669 69 70 73 747 26
C97 24 26 45 59 63 66
C10873 76 
C11977 80 81 845 33 55 
(A) IMGT reference pMHC contact site results from one hundred and four pMHC-I 3D structures (30 with 8-amino acid peptides and 74 with 9-amino acid peptides. (B) IMGT reference pMHC contact site results from forty-four pMHC-II 3D structures with 9 amino acids in the groove.



Figure 4: IMGT pMHC contact sites of human HLA-A*0201 MHC-I and a 9-amino acid peptide side chains (1ao7) [26]. Upper section: 3D structure of the human HLA-A*0201 groove. Lower section: IMGT pMHC contact sites IMGT Collier de Perles. Both views are from above the cleft, with G-ALPHA1 on top and G-ALPHA2 on bottom. In the box, C1 to C11 refer to contact sites. 1 to 9 refers to the numbering of the peptide amino acids P1 to P9. There are no C2 and C7 in MHC-I 3D structures with 9-amino acid peptides. There is no C5 in this 3D structure as P4 does not contact MHC amino acids (4G is shown between parentheses in the box).


C1 to C11 refers to the eleven contact sites. 1 to 9 refers to the numbering of the peptide amino acids in the groove. The peptide binding mode to MHC-I is characterized by the N and C peptide ends docked deeply with C1 and C11 contact sites that correspond to the two conserved pockets A and F, and by the peptide length that mechanically constrains the peptide conformation in the groove. There are no C2, C7 and C8 contact sites for MHC-I with 8-amino acid peptides, no C2 and C7 for MHC-I with 9-amino acid peptides. In contrast, for MHC-II, C2 is present but there is no C7 and C8. Whereas C1 and C11 correspond to the conserved pockets A and F, respectively, the correspondence between the other contact sites and the previously defined pockets is more approximative. For MHC-I with a peptide of 8-amino acids C3, C4, C6 and C9 correspond roughly to the B, D, C and E pockets, and for MHC-I with a peptide of 9-amino acids C3, C4 and C9 correspond to the B, D and E pockets.



Figure 5: IMGT pMHC contact sites of mouse H2-K1*01 MHC-I and a 8-amino acid peptide side chains (1jtr) [27]. Upper section: 3D structure of the mouse H2-K1*01 groove. Lower section: IMGT pMHC contact sites IMGT Collier de Perles. Both are views from above the cleft with G-ALPHA1 on top and G-ALPHA2 on bottom. In the box, C1 to C11 refer to contact sites, 1 to 8 refer to the numbering of the peptide amino acids P1 to P8. There are no C2, C7 and C8 in MHC-I 3D structures with 8-amino acid peptides. There is no C5 in this 3D structure as P4 does not contact MHC amino acids (4K is shown between parentheses in the box).


Figure 6: IMGT pMHC contact sites of human HLA-DRA*0101 and HLA-DRB1*0401 MHC-II and the peptide side chains (9 amino acids located in the groove) (1j8h) [23]. Upper section: 3D structure of the human HLA-DRA*0101 and HLA-DRB1*0401 groove. Lower section: IMGT pMHC contact sites IMGT Collier de Perles. Both are views from above the cleft with G-ALPHA on top and G-BETA on bottom. In the box, C1 to C11 refer to contact sites. 1 to 9 refers to the numbering of the peptide amino acid 1 to 9 located in the groove. There are no C7 and C8 in MHC-II 3D structures with peptide of 9 amino acids located in the groove. There is no C5 in this 3D structure as 5 does not contact MHC amino acids (5N is shown between parentheses in the box).




TR/pMHC 3D structures

Eighteen TR/pMHC 3D structures are available in IMGT/3Dstructure-DB [5] (Table 4). Fourteen 3D structures (twelve TR/pMHC-I and two TR/pMHC-II) comprise the complete extracellular region of the alpha-beta TR (TR-ALPHA_BETA) whereas four 3D structures comprise a Fv variable fragment (FV-ALPHA_BETA).

Table 4: T cell receptor/peptide/MHC (TR/pMHC) complexes in IMGT/3Dstructure-DB, http://imgt.cines.fr [5].
(A)TR/pMHC-I
  T cellreceptorPeptideMHC-II  
CodeRefNameSpV-DOMAIN genesCDR-IMGTSequenceLength SpGene and alleleR(Å)
1ao726A6HsTRAV12-2-TRAJ24[6.5.11]LLFGYPVYV9 HsHLA-A*02012.6
   HsTRBV6-5-TRBD2-TRBJ2-7[5.6.14]     
1qrn29A6  LLFGYAVYV9   2.80
1qse29A6  LLFGYPRYV9   2.80
1qsf29A6  LLFGYPVAV9   2.80
1bd230B7HsTRAV29/DV5-TRAJ54[6.6.10]LLFGYPVYV9 HsHLA-A*02012.5
 HsTRBV6-5-(TRBD2)-TRBJ2-7[5.6.13]      
1oga22JM22HsTRAV27-TRAJ42[5.6.10]GILGFVFTL9 HsHLA-A*02011.4
  HsTRBV19-(TRBD2)-TRBJ2-7[5.6.11]      
1mi54LC13HsTRAV26-2-TRAJ52[7.4.14]FLRGRAYGL9 HsHLA-B*08012.50
 HsTRBV7-8-(TRBD2)-TRBJ2-7[5.6.11]     
1lp93112.2MmTRAV12D-2-TRAJ50[6.6.13]ALWGFFPVL9 HsHLA-A*02012.00
 MmTRBV13-3-(TRBD2)-TRBJ2-7[5.6.11]     
1g6r322CMmTRAV9-4-TRAJ35[6.7.10]SIYRYYGL8MmH2-K1*012.80
 MmTRBV13-2-(TRBD2)-TRBJ2-4[5.6.9]     
1jtr272C   EQYKFYSV8   2.40
2ckb332C   EQYKFYSV8   3.2
1mwa272C   EQYKFYSV8  2.40
1fo034BM3.3MmTRAV16-TRAJ32[7.7.14]INFDFNTI8 MmH2-K1*012.50
 MmTRBV1-TRBD1-TRBJ1-3[6.6.12]     
1nam35BM3.3   RGYVYQGL8   2.70
1kj236KB5-C20MmTRAV14-1-TRAJ15[6.6.11]KVITFIDL8 MmH2-K1*012.71
 MmTRBV1-TRBD2-TRBJ2-3[6.6.16]     
(B)TR/pMHC-II
  T cellreceptorPeptideMHC-II  
CodeRefNameSpV-DOMAIN genesCDR-IMGTSequenceLength SpGene and alleleR(Å)
1fyt37HA1.7HsTRAV8-4-TRAJ48[6.7.13]PKYVKQNTLKLAT 13HsHLA-DRA*01012.60
HsTRBV28-TRBD1-TRBJ1-2[5.6.12]Hs HLA-DRB1*0101
1j8h23HA1.7  PKYVKQNTLKLAT13 HsHLA-DRA*01012.40
        HsHLA-DRB1*0401 
1d9k38D10MmTRAV14D-2-TRAJ4[6.6.10]GNSHRGAIEWEGIESG 16MmH2-AA*023.2
 MmTRBV13-2-TRBD2-TRBJ2-1[5.6.11]   MmH2-AB*02 
Sp: species, Hs: Homo sapiens, Mm: Mus musculus, R(Å): Crystallographic resolution in angstrom. Twelve 3D structures (10 TR/pMHC-I and 2 TR/pMHC-II) correspond to "complete" TR receptors (TR-ALPHA_BETA). Four 3D structures (1d9k, 1fo0, 1kj2 and 1nam) correspond to an Fv variable fragment (FV-ALPHA_BETA). Gene and allele names are according to IMGT/GENE-DB [18] for human and mouse TR, to IMGT/HLA-DB [17] for human MHC, and to MGD [13] and IMGT for mouse MHC. Amino acid sequences of the TR V-DOMAINs and MHC G-DOMAINs are reported in Figure 3 and Figure 4, respectively. H2-K1*01 encodes H2-K1b, H2-AB*02 and H2-AA*02 encode I-Abk and I-Aak, respectively. Between brackets, lengths of the CDR-IMGT are according to Lefranc et al. 2005 [15].


The IMGT Protein display (Figure 7) shows the amino acid sequences of the different V-ALPHA and V-BETA domains found in the crystallized TR/pMHC. Lengths of the V-DOMAIN CDR-IMGT from available TR/pMHC 3D structures are reported in Table 4, together with the names of the V, D and J genes [1]. For examples, the 1ao7 V-ALPHA [6.5.11] results from the TRAV12-2–TRAJ24 rearrangement, and the 1ao7 V-BETA [5.6.14] results from the TRBV6-5–TRBD2–TRBJ2-7 rearrangement. The amino acid sequences of the different G-DOMAINs found in the crystallized TR/pMHC are shown in the IMGT Protein display (Figure 8).



Figure 7: IMGT Protein display of the TR V-ALPHA and V-BETA domains found in the TR/pMHC complexes in IMGT/3Dstructure-DB [5, http://imgt.cines.fr. Amino acid sequences and gaps (shown by dots) are according to the IMGT unique numbering for V-DOMAIN [14]. The three additional positions in the CDR3-IMGT are 111.1, 112.2 and 112.1. Potential N-glycosylation sites are underlined. Assignments of the V, D and J genes are shown in Table 1.

Figure 8: Protein display of the G-DOMAINs found in the TR/pMHC complexes in IMGT/3Dstructure-DB, http://imgt.cines.fr [5]. Amino acid sequence and gaps (shown by dots) are according to the IMGT unique numbering for G-DOMAIN. Amino acid resulting from the splicing with the preceding exon are shown within parentheses. Potential N-glycosylation sites are underlined. The gap in 54A corresponds to a position that is characteristic of the MhcSF G-ALPHA1-LIKE domain [16]. Positions 61A, 61B and 72A are characteristic of the G-ALPHA2 and G-BETA domains.The corresponding gaps in G-ALPHA1 and G-ALPHA, shown in this IMGT Protein display, are not reported in the IMGT Colliers de Perles for as these gaps are shared by those two domains. H2-K1*01 encodes H2-K1b, H2-AB*02 and H2-AA*02 encode I-Abk and I-Aak, respectively.




TR/MHC and TR/peptide interfaces

The analysis of the pairwise contacts that occur at the TR/MHC and TR/peptide interfaces was carried out using the IMGT unique numbering for V-DOMAINs [14] for the TR, and the IMGT unique numbering for G-DOMAINs for the MHC. Table 5 shows the interactions of the TR V-ALPHA and TR V-BETA with MHC-I and the peptide, in nine TR/pMHC-I 3D structures. Table 6 shows the interactions of the TR V-ALPHA and TR V-BETA with MHC-II and the peptide, in two TR/pMHC-II 3D structures. These tables provide for the first time the contacts using the IMGT unique numbering for V-DOMAIN [14] and the IMGT unique numbering for G-DOMAIN [16], allowing to compare data whatever the gene group (TRAV, TRBV), the MHC class (MHC-I, MHC-II), and whatever the species (Homo sapiens, Mus musculus).

The results show that positions implicated in the binding are well conserved but not the pairwise interactions. The MHC contact positions belong to the G-DOMAIN helices. The TR positions that are involved in the contacts belong mostly to the CDR-IMGT and to anchor positions (shown by squares in Figure 2). The FR-IMGT positions involved in the contacts are positions 84 and 84A that are located at the DE turn (designated as "hypervariable 4" or HV4).

The contact analysis confirms that the V-ALPHA CDR2-IMGT seats on top of the G-ALPHA2 (MHC-I) or G-BETA (MHC-II) helices, and that the V-BETA CDR2-IMGT seats on top of the G-ALPHA1 (MHC-I) or G-ALPHA (MHC-II) helices (Tables 5 and 6). This agrees with data from Lau and Karplus 1994 [39] who showed that most of the TR/MHC specificity comes from the CDR1 and CDR2 because mutations in these CDRs are able to change specificity between MHC-I and MHC-II. V-ALPHA and V-BETA CDR3-IMGT usually follow the same G-DOMAIN contact preference as the CDR2-IMGT but they can also have contacts with the other G-DOMAINs. For example, in the 1oga 3D structure [22], position 66 of G-ALPHA2 is contacted by the V-ALPHA CDR3-IMGT but also by the V-BETA CDR3-IMGT.

Table 5: TR V-ALPHA and V-BETA CDR interactions with pMHC-I. (A) V-ALPHA CDR-IMGT interactions, (B) V-BETA CDR-IMGT interactions, (C) V-ALPHA and V-BETA FR-IMGT interactions.
(A) V-ALPHA CDR-IMGT interactions
V-ALPHA CDR1-IMGT
 CDR1 G-ALPHA1 Peptide G-ALPHA2
1ao7 [6.]27D 58E  
28R58E 77W 80R
29G 1L77W
31Q66K1L 2L 3F 4G 5Y70Y 73T
32S 5Y 
1bd2 [6.]28S 1L76E 77W
29M58E 59Y 62G 63E 66K1L77W
31D66K4G 5Y66Q 73T
32Y 5Y66Q
1oga [5.]30S  65E 66Q
1mi5 [7.]29S62R  
30G  69A
31T 4G66Q 70Y 73T
33Y 7Y61AA 62R 63V 64A 65E 66Q
1lp9 [6.]28T  76E
29Y  69A 72AG 73T 76E 77W
30S  69A
32F  65E 66Q 69A
1g6r [6.]27Y62R  
28S58E 62R  
29A62R  
30T  76E
32Y 3Y 4R66R
1jtr [6.]27Y62R  
28S58E 62R  
29A62R1E77W
30T  76E
32Y 3Y 4K66R
1fo0 [7.]28Q58E 62R  
29D62R  
30S  73T
31S  69A
33F  66R
1kj2 [6.]27D58E 62R  
29T62R1K77W
31N   73T
V-ALPHA CDR2-IMGT
 CDR2G-ALPHA1PeptideG-ALPHA2
1ao7 [.5.]57Y  65E 66Q 69A
58S  69A
59N  76E
1bd2 [.6.]57S  65E 66Q 69A
58S  69A 70Y 73T
59I  68R 69A 72E 72AG
1oga [.6.]57V  62H 65E
1mi5 [.4.]56G  62R
57L  65E 66Q 69A
58T  65E
59S  65E
1lp9 [.6.]57F  61AA 62H 65E 66Q
58T  62H 65E
61K  65E
1g6r [.7.]57Y  66R 69A
58S  69A 72AG 73T 76E
1jtr [.7.]57Y  65E 66R 69A 73T
58S  69A 70Y 72AG 73T
1fo0 [.7.]59Y  62G 65E 66R 69A
60K  65E
1kj2 [.6.]57R  69A 72E
58S  76E
59V  72E 72AG 76E
V-ALPHA CDR3-IMGT
 CDR3 G-ALPHA1 Peptide G-ALPHA2
1ao7 [.11]108T65R 66K4G 5Y 
109D62G 65R 66K4G 5Y 
110S 4G 5Y 6P 
113W65R 68K 69A 72Q    
114G 65R   
1bd2 [.10]107M  5Y  
108E 58E 62G 65R 66K   
109G 65R 66K 4G 5Y  
113A  4G 5Y  
114Q 65R 69A   
115K 65R   
1oga [.10]107A   66Q
108G  5F 66Q
109S  4G 5F 66Q
113Q 66K 4G 5F  
1mi5 [.14]108L  6A 7Y 66Q
109A 62R   
110G 62R 66I   
111G 65Q 66I 69T 4G  
112S 69T 6A  
112.1T 62R 65Q 66I 69T   
113Y 69T 72Q 6A  
1lp9 [.13]107F  5F 66Q
109A  3W 4G 5F 66Q
110S  2L 3W 4G 66Q 69A 70Y 73T
111S 63E 66K 2L 4G 73T 77W
112S 66K 4G 5F  
113F 65R 66K 69A 4G 6F  
114S  4G 5F 6F 
1g6r [.10]107S  4R  
108G  4R  
109F 62R 65Q 66K 4R  
113A  4R  
114S  4R  
1jtr [.10]107S  4K  
108G 66K 4K  
109F 61E 62R 65Q 66K 4K  
113A  4K  
114S  4K  
1fo0 [.14]110Y 65Q   
111G 65Q   
112.1G 65Q   
1kj2 [.11]108Y 62R   
109Q 63E 66K 1K 2V 3I 4T 70Y 73T
110G 66K 4T  
114R 65Q 68K 69G 72Q   
(B) V-BETA CDR-IMGT interactions
V-BETA CDR1-IMGT
 CDR1 G-ALPHA1 PeptideG-ALPHA2
1ao7 [5.]30E  8Y  
1oga [5.]30D  8T 58K
1mi5 [5.]30V 76E 80N   
31S 76E   
1lp9 [5.]30D 72Q 76V   
31Y 69A 73T 6F  
1g6r [5.]28N  6Y 58K
29H  6Y 61Q 61AA
30N  6Y 7G 8L 58K
31N  6Y 
1jtr [5.]27N   61Q
28N  6Y 58K 61Q
29H  6Y 61Q 61AA
30N  6Y 7S 8V 58K 59W
31N  6Y 
1fo0 [6.]29Q   61Q
32W76V7T 
1kj2 [6.]29Q   58K 59W 61Q 61AA
30Y   61AA
31P  7D 
32W 69G 72Q   
V-BETA CDR2-IMGT
 CDR2 G-ALPHA1 Peptide G-ALPHA2
1bd2 [.6.]61I 72Q   
1oga [.6.]57Q 69A 4G 5F 6V  
58I 69A 72Q 73T 76V 6V 8T  
59V 72Q 76V   
60N 72Q 75R   
61D 65R 68K 69A 72Q   
1mi5 [.6.]57Q 72Q 75R 76E   
58N 79R   
59E 79R   
1lp9 [.6.]57Y 65R 68K 69A 72Q   
58V 72Q   
61S 68K   
1g6r [.6.]57Y 69G 70N 72Q 73S 76V   
58G 76V   
59A 76V 79R   
60G 79R   
61S 76V   
1jtr [.6.]57Y 69G 72Q 73S 76V 7S  
58G 76V   
59A 79R   
60G 79R   
61S 76V 79R   
1fo0 [.6.]57R 76V 79R 80T   
58S 76V 79R   
59P 79R   
1kj2 [.6.]57R 72Q 73S 76V 7D  
58S 72Q   
61D 72Q   
V-BETA CDR3-IMGT
 CDR3 G-ALPHA1 Peptide G-ALPHA2
1ao7 [.14]107R  5Y  
109G  6P 
110L 69A 72Q 73T 6P 7V 8Y  
111A  7V 8Y 61AA
112G  5Y 7V 61AA 62H 63V 66Q
112.1G  5Y 7V 61AA
113R  5Y 61A 61AA 62H 66Q
114P  5Y 66Q
1bd2 [.13]108Y  8Y  
109P  6P 7V 
110G  6P 7V 8Y 
111G  7V 8Y 61AA
112G  7V 61AA
114Y  5Y 7V 61AA 63V 66Q
1oga [.11]108S   61AA
109R  5F 6V 7F 61AA 62H 63V 66Q
110S  5F 6V 66Q
113S  5F 66Q
114Y   61A 61AA 62H
1mi5 [.11]108L 76E  58K
109G 76E   
110Q 69T 72Q 73T 76E 5R 6A  
113A  6A 7Y 
114Y 76E 7Y 8G 58K 59W 61AA
1lp9 [.11]109W  5F 6F 7P 8V 58K 59W 61AA 63V
110V  5F 61AA
113S  5F  
114Y  5F 61A 61AA 62H 66Q
1g6r [.9]107G  6Y  
108G  6Y 61AA 63E
109G  4R 6Y 61AA 66R
114G  4R 66R
115T   61AA
1jtr [.9]107G  6Y  
108G  6Y 61AA 63E 66R
109G  6Y 63E 66R
114G   66R
1fo0 [.12]108A   58K
109D  6N 7T 58K 59W
110R 69G 70N 72Q 73S 4D 5F 6N  
112V  4D 5F 6N 66R
113G  6N  
114N  6N 61AA
1kj2 [.16]108A  6I 66R
109A  4T 6I 66R
110P  4T  
111D  4T 66R
111.1W   62G 65E 66R 69A
112S   61Q 61AA
112.1A   61AA
114E   69A
(C) V-ALPHA and V-BETA FR-IMGT interactions
V-ALPHA FR-IMGT V-BETA FR-IMGT
  Position G-ALPHA1 Peptide G-ALPHA2   Position G-ALPHA1 Peptide G-ALPHA2
1ao7 2K 58E     1bd2 55Y 65R    
26S 58E     67D 68K    
84AK     73T 76E 1oga 67Q 65R    
1bd2 2Q 58E 65R     1mi5 55Y 72Q 76E    
84AK     72AG 73T 66L 72Q 75R    
1oga 84CR     65E 1lp9 55Y 65R    
1mi5 40H   7Y   67E 65R 68K    
52Y     62R 1g6r 67E 72Q    
55H   7Y 61AA 62R 84Q     58K
67V     62R 1jtr 67E 72Q    
1lp9 84AK     65E 84Q     58K
1g6r 2Q   4R  
55K     65E
1jtr 55K     65E
84AK     76E
1kj2 84AK     76E
TR positions in bold indicate hydrogen bonds. Three dimensional (3D) structures are from IMGT/3Dstructure-DB [5], http://imgt.cines.fr. Lengths of the CDR-IMGT are shown within brackets. Amino acids are shown in the one-letter code. Sequences of the peptides are reported in Table 4, sequences of the TR V-ALPHA and V-BETA domains in Figure 7 and sequences of the MHC-I G-ALPHA1 and G-ALPHA2 in Figure 8.


Table 6: V-ALPHA and V-BETA CDR interactions with MHC-II. (A) V-ALPHA CDR-IMGT interactions, (B) V-BETA CDR-IMGT interactions, (C) V-ALPHA and V-BETA FR-IMGT interactions.
(A) V-ALPHA CDR-IMGT interactions
V-ALPHA CDR1-IMGT
 Position G-ALPHA Peptide G-BETA
1j8h [6.]28S  2K 76H
29V  2K 4V 76H
30P  4V 72AT 76H
32Y   72AT
1d9k [6.]27D  3S  
28S   72AT 76H
29T  3S 4H 5R 72AT 76H
30F  5R 72AT
31D  5R 8I 66R 69A 72AT
32Y   66R
V-ALPHA CDR2-IMGT
 Position G-ALPHA Peptide G-BETA
1j8h [.7.]57T   65E
58S   69A 72AT
59A   65E
1d9k [.6.]57S   65E 66R 69A
58L   69A 72D 72AT
59V   65E 66R 68R 69A
60S   65E
V-ALPHA CDR3-IMGT
 Position G-ALPHA Peptide G-BETA
1j8h [.13]108E 63E 2K 4V  
110P  7N 66Q
111F  7N 9L 62D 63L 66Q
114E 66G 69A 70N 5K  
1d9k [.10]107T   66R
108G  5R 8I 66R
109S 69Q 8I 66R
113F 69Q 73T 8I 9E 10W 11E 61BY 66R
114N 69Q  66R
115K 65Q   
(B) V-BETA CDR-IMGT interactions
V-BETA CDR-IMGT
 Position G-ALPHA Peptide G-BETA
1j8h [5.]27M 10K  
28D 76A 10K  
29H 10K  
30E 72A 73V 76A 10K  
31N 69A   
1d9k [5.]30N 76H   
31N 69Q   
V-BETA CDR2-IMGT
 Position G-ALPHAPeptide G-BETA
1j8h [.6.] 57Y 65Q 66G 68L 69A 72A   
58D 68L 72A 75 K   
61M 43K 68L   
1d9k [.6.]57Y 65Q 66G 68L 69Q 72A   
V-BETA CDR3-IMGT
 PositionG-ALPHAPeptideG-BETA
1j8h [.12]108S 73V 10K  
109T 69A 70N 73V 5K 7N 8T  
110G 73V 8T 9L 10 K  
112L  10K 58Y
113P   61AQ 62D 63L
1d9k [.11]108G  11E  
109Q  11E 58Y 61BY
110G  10W 11E 61BY 66R
113R   61K 61AQ 61BY 65E 66R
114A   66R
(C) V-ALPHA and V-BETA FR-IMGT interactions
V-ALPHA FR-IMGT
 PositionG-ALPHAPeptideG-BETA
1j8h55K   62D
1d9k84AK   72D
V-BETA FR-IMGT
 PositionG-ALPHAPeptideG-BETA
1j8h55F 65Q   
66K 43K   
67E 43K 65 Q   
84K 72A 76A 10K  
1d9k55Y 65Q   
66T 43K   
67E 43K 65Q 68L   
68K 65Q   
TR positions in bold indicate hydrogen bonds. Three dimensional (3D) structures are from IMGT/3Dstructure-DB5, http://imgt.cines.fr. Lengths of the CDR-IMGT are shown within brackets. Amino acids are shown in the one-letter code. Sequences of the peptides are reported in Table 4, sequences of the TR V-ALPHA and V-BETA domains in Figure 7, and sequences of the MHC-II G-ALPHA and G-BETA in Figure 8.


The diagonal orientation of the TR/pMHC complex puts the TR in a globally conserved position to "read-out" the peptide [31]. V-ALPHA is on top of the peptide N terminus while V-BETA is on top of the peptide C terminus. TR positions implicated in the peptide recognition are in the CDR3-IMGT and generally to a lesser extent in the V-ALPHA CDR1-IMGT (Tables 5 and 6). Nearly every 3D structure shows different CDR3 conformations and binding mode. In the JM22/peptide/HLA-A complex (1oga) [22], the V-BETA CDR3-IMGT extensively contacts the peptide and G-ALPHA2 through hydrogen bonds (Table 5), by inserting itself between the peptide and the G-ALPHA2. In contrast, the 2C/peptide/H2-K1 complex (1jtr) [27] has comparatively fewer contacts between the V-BETA CDR3-IMGT and the peptide and the MHC, however the V-BETA CDR1-IMGT has more contacts and hydrogen bonds with the peptide and G-ALPHA2.

The TR LC13 and 2C were crystallized both alone and in complex with a pMHC. The structural superimposition of both V-DOMAIN scaffold alpha carbons reveals large movements of the CDR3 and of the CDR1, respectively. The V-ALPHA domains of LC13, in the 1mi5 and 1kgc 3D structures, have 3.5Å root mean square (RMS) between their CDR3. The V-ALPHA domains of 2C, in the 2ckb and 1tcr 3D structures, have 2.3Å RMS between their CDR1. The TR A6 was crystallized in complex with the same MHC but with different peptides. In these structures, the V-BETA CDR3 adopt different conformations to adapt to the different peptides [40]. The CDR3 conformational change does not increase the binding surface but gives a better shape complementarity to the interface [41].



Conclusion

The 3D structure of the MHC main chain is well conserved and the peptide binding groove specificity is due to side chains physicochemical characteristics [38]. Both MHC-I and MHC-II grooves have pockets where side chains of bound peptides may anchor [42], the specificity of a peptide to a given MHC being controlled by the physicochemical properties of the pockets. Conversely comparison of peptide sequence alignments and pMHC 3D structures have revealed that some anchored peptide positions with conserved properties were needed to bind a peculiar MHC allele. Several databases, SYFPEITHI [43], JenPep [44] and MHCpep [45], provide peptide sequences associated with MHC alleles together with anchor positions and experimental data on affinity. These observations have extensively been used in peptide/MHC binding prediction [46, 47, 48] (a list of prediction programs and servers is available at "The IMGT Immunoinformatics page", http://imgt.cines.fr). Nevertheless exceptions have been found [49, 50, 51] and it has been noted that only 30% of peptides with the expected pattern really bind whereas some peptides without the expected pattern do bind [52]. Peptide/MHC binding prediction and epitope prediction remain a big challenge. In order to compare interactions between MHC domains of classes I and II and with peptides of different lengths, we have defined eleven IMGT pMHC contact sites which are based on the IMGT unique numbering for G-DOMAIN and G-LIKE-DOMAIN [16]. IMGT contact sites allow comparison either with the IMGT reference pMHC contact sites, or with other IMGT contact sites. They also allow to underline the impact of mutations of altered peptides, such as the ones observed in altered Tax peptide in 1qsf and 1qse [29]. IMGT pMHC contact sites are available for all the pMHC and TR/pMHC in IMGT/3Dstructure-DB [5], http://imgt.cines.fr.

With only 18 TR/pMHC 3D structures, the atomic details of TR/pMHC interactions already show a great deal of variability. IMGT standardization is a step towards a better understanding of the mechanisms ruling TR/pMHC recognition. It will help comparing new experimentally resolved 3D structures with published data. However the TR/pMHC interactions are far from being unravelled and the study of the TR/pMHC interactions with the other proteins of the immunological synapse will be crucial. For example, the interaction between a MHC and the CD4 considerably enhances the pMHC/TR sensibility [53, 54]. The understanding of the T cell triggering early events is subject to active studies.

Although the TR/pMHC binding represents a necessary step for the TR recognition, many factors, the TR affinity for the pMHC, the relocation of surface proteins such as CD4 or CD8 in the immunological synapse are necessary for generating the T cell activation signal. Each of these steps needs to be described and characterized so that data from different experiments can be integrated. IMGT standardization will be further extended on the IMGT Web site at http://imgt.cines.fr as new parameters will become available.



Citing IMGT/3Dstructure-DB

Users are requested to cite reference 5 and this article, and to quote the IMGT home page URL, http://imgt.cines.fr.



Acknowledgements

We are grateful to the IMGT team for helpful discussion. K. Q. was the recipient of a doctoral grant from the Ministère de l'Education Nationale, de l'Enseignement Supérieur et de la Recherche (MENESR) and is currently supported by a grant from the Association pour la Recherche sur le Cancer (ARC). IMGT is a registered Centre National de la Recherche Scientifique (CNRS) mark. IMGT is a National RIO Bioinformatics Platform since 2001 (CNRS, INSERM, CEA, INRA). IMGT was funded in part by the BIOMED1 (BIOCT930038), Biotechnology BIOTECH2 (BIO4CT960037) and 5th PCRDT Quality of Life and Management of Living Resources (QLG2-2000-01287) programmes of the European Union and received subventions from ARC and from the Génopole-Montpellier-Languedoc-Roussillon. IMGT is currently supported by the CNRS, the MENESR (Université Montpellier II Plan Pluri-Formation, BIOSTIC-LR2004 Région Languedoc-Roussillon and ACI-IMPBIO IMP82-2004), and GIS-AGENAE. Part of this work was carried out in the frame of the European Science Foundation Scientific Network Myelin Structure and its role in autoimmunity (MARIE).




References


  1. Lefranc, M.-P. and Lefranc, G. (2001). The T cell receptor FactsBook. Academic Press, London, UK, 398 pages.
    http://imgt.cines.fr/textes/IMGTindex/factsbook.html

  2. Vasmatzis, G., Cornette, J., Sezerman, U. and DeLisi, C. (1996). TcR recognition of the MHC-peptide dimer: structural properties of a ternary Complex. J. Mol. Biol. 261, 72-89.

  3. Sim, B. C., Zerva, L., Greene, M. I. and Gascoigne, N. R. (1996). Control of MHC restriction by TCR Valpha CDR1 and CDR2. Science 273, 963-966.

  4. Kjer-Nielsen, L., Clements, C. S., Purcell, A. W., Brooks, A. G., Whisstock, J. C., Burrows, S. R., McCluskey, J. and Rossjohn, J. (2003). A structural basis for the selection of dominant alphabeta T cell receptors in antiviral immunity. Immunity 18, 53-64.

  5. Kaas, Q., Ruiz, M. and Lefranc, M.-P. (2004). IMGT/3Dstructure-DB and IMGT/StructuralQuery, a database and a tool for immunoglobulin, T cell receptor and MHC structural data. Nucleic Acids Res. 32, D208-D210.

  6. Berman, H. M., Westbrook, J., Feng, Z., Gilliland, G., Bhat, T. N., Weissig, H., Shindyalov, I. N. and Bourne, P. E. (2000). The Protein Data Bank. Nucleic Acids Res. 28, 235-242.

  7. Lefranc, M.-P., Giudicelli, V., Kaas, Q., Duprat, E., Jabado-Michaloud, J., Scaviner, D., Ginestoux, C., Clément, O., Chaume, D. and Lefranc, G. (2005). IMGT, the international ImMunoGeneTics information system®. Nucleic Acids Res. 33, D593-D597.

  8. Lefranc, M.-P., Clément, O., Kaas, Q., Duprat, E., Chastellan, P., Coelho, I., Combre, K., Ginestoux, C., Giudicelli, V., Chaume, D. and Lefranc, G. (2004). IMGT-Choreography for Immunogenetics and Immunoinformatics. In Silico Biol. 5, 0006.

  9. Lefranc, M.-P., Giudicelli, V., Ginestoux, C., Bosc, N., Folch, G., Guiraudou, D., Jabado-Michaloud, J., Magris, S., Scaviner, D., Thouvenin, V., Combres, K., Girod, D., Jeanjean, S., Protat, C., Yousfi Monod, M., Duprat, E., Kaas, Q., Pommié, C., Chaume, D. and Lefranc, G. (2003). IMGT-ONTOLOGY for immunogenetics and immunoinformatics. In Silico Biol. 4, 0004.

  10. Lefranc, M.-P. (2004). IMGT-ONTOLOGY and IMGT databases, tools and Web resources for immunogenetics and immunoinformatics. Mol. Immunol. 40, 647-660.

  11. Giudicelli, V. and Lefranc, M.-P. (1999). Ontology for immunogenetics: the IMGT-ONTOLOGY. Bioinformatics 15, 1047-1054.

  12. Wain, H. M., Bruford, E. A., Lovering, R. C., Lush, M. J., Wright, M. W. and Povey, S. (2002). Guidelines for human gene nomenclature. Genomics 79, 464-470.

  13. Blake, J. A., Richardson, J. E., Bult, C. J., Kadin, J. A. and Eppig, J. T. (2003). MGD: the Mouse Genome Database. Nucleic Acids Res. 31, 193-195.

  14. Lefranc, M.-P., Pommié, C., Ruiz, M., Giudicelli, V., Foulquier, E., Truong, L., Thouvenin-Contet, V. and Lefranc, G. (2003). IMGT unique numbering for immunoglobulin and T cell receptor variable domains and Ig superfamily V-like domains. Dev. Comp. Immunol. 27, 55-77.

  15. Lefranc, M.-P., Pommié, C., Kaas, Q., Duprat, E., Bosc, N., Guiraudou, D., Jean, C., Ruiz, M., Da Piedade, L., Rouard, M., Foulquier, E., Thouvenin, V. and Lefranc, G. (2005). IMGT unique numbering for immunoglobulin and T cell receptor constant domains and Ig superfamily C-like domains. Dev. Comp. Immunol. 29, 185-203.

  16. Lefranc, M.-P., Duprat, E., Kaas, Q., Tranne, M., Thiriot, A. and Lefranc, G. (2005). IMGT unique numbering for MHC groove G-DOMAIN and MHC superfamily (MhcSF) G-LIKE-DOMAIN. Dev. Comp. Immunol. 29, 917-938.

  17. Robinson, J., Waller, M. J., Parham, P., de Groot, N., Bontrop, R., Kennedy, L. J., Stoehr, P. and Marsh, S. G. (2003). IMGT/HLA and IMGT/MHC: sequence databases for the study of the major histocompatibility complex. Nucleic Acids Res. 31, 311-314.

  18. Giudicelli, V., Chaume, D., Lefranc, M.-P. (2005). IMGT/GENE-DB: a comprehensive database for human and mouse immunoglobulin and T cell receptor genes. Nucleic Acids Res. 33, D256-D261.

  19. Giudicelli, V., Chaume, D. and Lefranc, M.-P. (2004). IMGT/V-QUEST, an integrated software program for immunoglobulin and T cell receptor V-J and V-D-J rearrangement analysis. Nucleic Acids Res. 32, W435-W440.

  20. Yousfi Monod, M., Giudicelli, V., Chaume, D. and Lefranc, M.-P. (2004). IMGT/JunctionAnalysis: the first tool for the analysis of the immunoglobulin and T cell receptor complex V-J and V-D-J JUNCTIONs. Bioinformatics 20, I379-I385.

  21. Lesk, A. M. and Chothia, C. (1982). Evolution of proteins formed by beta-sheets. II. The core of the immunoglobulin domains. J. Mol. Biol. 160, 325-342.

  22. Stewart-Jones, G. B. E., McMichael, A. J., Bell, J. I., Stuart, D. I. and Jones, E. Y. (2003). A structural basis for immunodominant human T cell receptor recognition. Nat. Immunol. 4, 657-663.

  23. Hennecke, J. and Wiley, D. C. (2002). Structure of a complex of the human alpha/beta T cell receptor (TCR) HA1.7, influenza hemagglutinin peptide, and major histocompatibility complex class II molecule, HLA-DR4 (DRA*0101 and DRB1*0401): insight into TCR cross-restriction and alloreactivity. J. Exp. Med. 195, 571-581.

  24. Wang, J. H., Meijers, R., Xiong, Y., Liu, J. H., Sakihama, T., Zhang, R., Joachimiak, A. and Reinherz, E. L. (2001). Crystal structure of the human CD4 N-terminal two-domain fragment complexed to a class II MHC molecule. Proc. Natl. Acad. Sci. USA 98, 10799-10804.

  25. Wang, J. H. and Reinherz, E. L. (2002). Structural basis of T cell recognition of peptides bound to MHC molecules. Mol. Immunol. 38, 1039-1049.

  26. Garboczi, D. N., Ghosh, P., Utz, U., Fan, Q. R., Biddison, W. E. and Wiley, D. C. (1996). Structure of the complex between human T-cell receptor, viral peptide and HLA-A2. Nature 384, 134-141.

  27. Luz, J. G., Huang, M., Garcia, K. C., Rudolph, M. G., Apostolopoulos, V., Teyton, L. and Wilson, I. A. (2002). Structural comparison of allogeneic and syngeneic T cell receptor-peptide-major histocompatibility complex complexes: a buried alloreactive mutation subtly alters peptide presentation substantially increasing V(beta) Interactions. J. Exp. Med. 195, 1175-1186.

  28. Zhang, C., Anderson, A. and DeLisi, C. (1998). Structural principles that govern the peptide-binding motifs of class I MHC molecules. J. Mol. Biol. 281,929-947.

  29. Ding, Y. H., Baker, B. M., Garboczi, D. N., Biddison, W. E. and Wiley, D. C. (1999). Four A6-TCR/peptide/HLA-A2 structures that generate very different T cell signals are nearly identical. Immunity 11, 45-56.

  30. Ding, Y. H., Smith, K. J., Garboczi, D. N., Utz, U., Biddison, W. E. and Wiley, D. C. (1998). Two human T cell receptors bind in a similar diagonal mode to the HLA-A2/Tax peptide complex using different TCR amino acids. Immunity 8, 403-411.

  31. Buslepp, J., Wang, H., Biddison, W. E., Appella, E. and Collins, E. J. (2003). A correlation between TCR Valpha docking on MHC and CD8 dependence: implications for T cell selection. Immunity 19, 595-606.

  32. Degano, M., Garcia, K. C., Apostolopoulos, V., Rudolph, M. G., Teyton, L. and Wilson, I. A. (2000). A functional hot spot for antigen recognition in a superagonist TCR/MHC complex. Immunity 12, 251-261.

  33. Garcia, K. C., Degano, M., Pease, L. R., Huang, M., Peterson, P. A., Teyton, L. and Wilson, I. A. (1998). Structural basis of plasticity in T cell receptor recognition of a self peptide-MHC antigen. Science 279, 1166-1172.

  34. Reiser, J. B., Darnault, C., Guimezanes, A., Gregoire, C., Mosser, T., Schmitt-Verhulst, A. M., Fontecilla-Camps, J. C., Malissen, B., Housset, D. and Mazza, G. (2000). Crystal structure of a T cell receptor bound to an allogeneic MHC molecule. Nat. Immunol. 1, 291-297.

  35. Reiser, J. B., Darnault, C., Gregoire, C., Mosser, T., Mazza, G., Kearney, A., van der Merwe, P. A., Fontecilla-Camps, J. C., Housset, D. and Malissen, B. (2003). CDR3 loop flexibility contributes to the degeneracy of TCR recognition. Nat. Immunol. 4, 241-247.

  36. Reiser, J. B., Gregoire, C., Darnault, C., Mosser, T., Guimezanes, A., Schmitt-Verhulst, A. M., Fontecilla-Camps, J. C., Mazza, G., Malissen, B. and Housset, D. (2002). A T cell receptor CDR3beta loop undergoes conformational changes of unprecedented magnitude upon binding to a peptide/MHC class I complex. Immunity 16, 345-354.

  37. Hennecke, J., Carfi, A. and Wiley, D. C. (2000). Structure of a covalently stabilized complex of a human alphabeta T-cell receptor, influenza HA peptide and MHC class II molecule, HLA-DR1. EMBO J. 19, 5611-5624.

  38. Reinherz, E. L., Tan, K., Tang, L., Kern, P., Liu, J., Xiong, Y., Hussey, R. E., Smolyar, A., Hare, B., Zhang, R., Joachimiak, A., Chang, H. C., Wagner, G. and Wang, J. (1999). The crystal structure of a T cell receptor in complex with peptide and MHC class II. Science 286, 1913-1921.

  39. Lau, F. T. and Karplus, M. (1994). Molecular recognition in proteins. Simulation analysis of substrate binding by a tyrosyl-tRNA synthetase mutant. J. Mol. Biol. 236, 1049-1066.

  40. Rudolph, M. G., Luz, J. G. and Wilson, I. A. (2002). Structural and thermodynamic correlates of T cell signaling. Annu. Rev. Biophys. Biomol. Struct. 31, 121-149.

  41. Lawrence, M. C. and Colman, P. M. (1993). Shape complementarity at protein/protein interfaces. J. Mol. Biol. 234, 946-950.

  42. Falk, K., Rotzschke, O., Stevanovic, S., Jung, G. and Rammensee, H.-G. (1991). Allele-specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature 351, 290-296.

  43. Rammensee, H.-G., Bachmann, J., Emmerich, N. P. N., Bachor, O. A. and Stevanovic, S. (1999). SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics 50, 213-219.

  44. Blythe, M. J., Doytchinova, I. A. and Flower, D. R. (2002). JenPep: a database of quantitative functional peptide data for immunology. Bioinformatics 18, 434-439.

  45. Brusic, V., Rudy, G. and Harrison, L. C. (1998). MHCPEP, a database of MHC-binding peptides: update 1997. Nucleic Acids Res. 26, 368-371.

  46. Singh, H. and Raghava, G. P. (2003). ProPred1: prediction of promiscuous MHC Class-I binding sites. Bioinformatics 19, 1009-1014.

  47. Adams, H. P. and Koziol, J. A. (1995). Prediction of binding to MHC class I molecules. J. Immunol. Methods 185, 181-190.

  48. Vasmatzis, G., Zhang, C., Cornette, J. L. and DeLisi, C. (1996). Computational determination of side chain specificity for pockets in class I MHC molecules. Mol. Immunol. 33, 1231-1239.

  49. Mandelboim, O., Bar-Haim, E., Vadai, E., Fridkin, M. and Eisenbach, L. (1997). Identification of shared tumor-associated antigen peptides between two spontaneous lung carcinomas. J. Immunol. 159, 6030-6036.

  50. Apostolopoulos, V., Yu, M., Corper, A. L., Teyton, L., Pieters, G. A., McKenzie, I. F. C. and Wilson, I. A. (2002). Crystal structure of a non-canonical Low-affinity Peptide Complexed with MHC Class I: A New approach for vaccine design. J. Mol. Biol. 318, 1293-1305.

  51. Scott, C. A., Peterson, P. A., Teyton, L. and Wilson, I. A. (1998). Crystal structures of two I-Ad-peptide complexes reveal that high affinity can be achieved without large anchor residues. Immunity 8, 319-329.

  52. Gulukota, K., Sidney, J., Sette, A. and DeLisi, C. (1997). Two complementary methods for predicting peptides binding major histocompatibility complex molecules. J. Mol. Biol. 267, 1258-1267.

  53. Irvine, D. J., Purbhoo, M. A., Krosgaard, M. and Davis, M. M. (2002). Direct observation of ligand recognition by T cells. Nature 419, 845-849.

  54. Davis, M. M. (2002). A new trigger for T cells. Cell 110, 285-287.