A New Twist in TCR Diversity Revealed by a Forbidden αβ TCR

McBeth, Christine; Seamons, Audrey; Pizarro, J.C.; Fleishman, Sarel J.; Baker, David; Kortemme, Tanja; Goverman, Joan; Strong, Roland K.

doi:10.1016/j.jmb.2007.11.020

Cited by 23 publications

(38 citation statements)

References 45 publications

(50 reference statements)

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“…Moreover, several studies have shown that mutations in CDR3 loops can have different effects on TCR/MHC interaction. Thus, CDR3 mutants occasionally acquire higher affinity for the ligand (25,26); however, more often, CDR3 mutants lose the ability to bind their ligands (16,27,28). These findings raise the question of whether the TCR CDR3 loops play an active or passive role in shaping the T-cell predisposition for MHC.…”

Section: Discussionmentioning

confidence: 99%

“…None of the clones in group C (clones [16][17][18][19] responded to any of the stimuli. These clones were primarily identified in the enriched transductants that carried more than 1 mutant CDR3, only 1 of which had IA b -3K or allo-MHC reactivity.…”

Section: Many Different V␤ Cdr3 Loops Support the Cross-reactivity Ofmentioning

confidence: 92%

“…However, neither 93D nor 98T made any contact with IA b -3K in the structure. These amino acids are on the beginning of the ␤ strands that support the V␤ CDR3 loop, and their mutation might affect the packing of these strands against the other ␤ strands of V␤ and influence the conformation of the tip of the CDR3 loop indirectly (16).…”

Section: Contribution Of the Cdr3 Loops Of The Yae62 Tcr To Its Broadmentioning

confidence: 99%

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Many different Vβ CDR3s can reveal the inherent MHC reactivity of germline-encoded TCR V regions

Rubtsova

Scott‐Browne

Crawford

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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We have hypothesized that in the prenegative selection TCR repertoire, many somatically generated complementary-determining region (CDR) 3 loops combine with evolutionarily selected germline V␣/V␤ CDR1/CDR2 loops to create highly MHC/peptide cross-reactive T cells that are subsequently deleted by negative selection. Here, we present a mutational analysis of the V␤ CDR3 of such a cross-reactive T-cell receptor (TCR), YAe62. Most YAe62 TCRs with the mutant CDR3s became less MHC promiscuous. However, others with CDR3s unrelated in sequence to the original recognized even more MHC alleles than the original TCR. Most importantly, this recognition was still dependent on the conserved CDR1/CDR2 residues. These results bolster the idea that germline TCR V elements are inherently reactive to MHC but that this reactivity is fine-tuned by the somatically generated CDR3 loops.major histocompatibility complex ͉ specificity ͉ T cell T he more than 3 dozen solved structures of T-cell receptor (TCR)/MHC complexes have shown that most TCRs bind to their MHC/peptide ligands, regardless of the MHC allele or class, in a similar diagonal mode, although there is some variation in the angle and pitch of engagement (1). We (2-5) and others (6, 7) have used this structural information and mutational analyses to tackle the question of whether TCRs have been evolutionarily selected to bind to MHC molecules. We focused on the TCR complementary-determining region (CDR) 1 and CDR2 loops, because, unlike the somatically generated CDR3 loops, CDR1s and CDR2s are fully encoded in the germline, and therefore susceptible to evolutionary selection. Also, in many TCR/MHC structures, these loops, especially CDR2s, are often the main source of contact with MHC (1,8,9).For MHCII, the best-documented example of this conserved interaction involves V␤ elements related to mouse V␤8. Analysis of 9 structures with multiple MHC alleles, different bound peptides, different V␣s, and different V␤ CDR3s has found that in the V␤8-like V␤s, 46Y, 48Y, and 54E (all in ␤CDR2) nearly always interact with the same conserved amino acids (␣1 39K, 57Q, 60L, 61Q, and 64A) on MHCII (3). The data suggest a similar situation for some V␣s (2, 3). For example, in a number of structures involving V␣ elements related to mouse V␣4, Y29 in the V␣ CDR1 loop interacts with a conserved site composed of MHCII ␤ 76D, 77T, and 81H (3). As more TCR/MHC structures appear, it is likely that additional conserved interactions will be found (3).In a series of functional and mutational studies, we examined T cells that develop in ''single peptide'' mice (i.e., mice whose MHCII is occupied by a single covalently attached peptide) (2, 4, 10-12). These mice contain many T cells that are highly peptide and MHC allele cross-reactive. We explained this by proposing that TCR V regions are biased to react with MHC; thus, the thymus produces a very high frequency of thymocytes bearing TCRs in which conserved V region CDR1/CDR2 interactions with MHCII are very strong, leading to highly degenerate MHC and...

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Section: Discussionmentioning

confidence: 99%

Section: Many Different V␤ Cdr3 Loops Support the Cross-reactivity Ofmentioning

confidence: 92%

Section: Contribution Of the Cdr3 Loops Of The Yae62 Tcr To Its Broadmentioning

confidence: 99%

See 1 more Smart Citation

Many different Vβ CDR3s can reveal the inherent MHC reactivity of germline-encoded TCR V regions

Rubtsova

Scott‐Browne

Crawford

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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show abstract

“…Secondly, a recent structure of another MBP reactive TCR (1.D9.B2) containing identical Va and Vb as the 172.10 (Va2.3, Vb8.2), but different CDR3 sequences, shows that the TCR cannot dock in the same orientation because the Va/Vb interdomain angle is significantly different from 172.10 and thus cannot interact with I-A b in the same way as predicted. A docked model produced by Rosetta [36] suggests a dramatically different docking orientation that does not include major Vb CDR1 and CDR2 contributions [37]. Thus, the demonstration of conserved contacts in the case of TCR/MHC II is tenuous.…”

Section: Mhc IImentioning

confidence: 99%

TCR-MHC docking orientation: natural selection, or thymic selection?

Collins

Riddle

2008

Immunol Res

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T cell receptors (TCR) dock on their peptide-major histocompatibility complex (pMHC) targets in a conserved orientation. Since amino acid sidechains are the foundation of specific protein-protein interactions, a simple explanation for the conserved docking orientation is that key amino acids encoded by the TCR and MHC genes have been selected and maintained through evolution in order to preserve TCR/pMHC binding. Expectations that follow from the hypothesis that TCR and MHC evolved to interact are discussed in light of the data that both support and refute them. Finally, an alternative and equally simple explanation for the driving force behind the conserved docking orientation is described.

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“…Even more important, of the several MHC II-peptide-TCR complexes, there have been a few characteristic of a specific autoimmune disease [39][40][41][42][43][44]. It is essential first to analyse the MHC II-peptide interactions in such autoantigenic complexes in order to appreciate the intricacies involved.…”

Section: The Mhc Ii-peptide-tcr Complexmentioning

confidence: 99%

Use of MHC II Structural Features in the Design of Vaccines for Organ-Specific Autoimmune Diseases

Moustakas

Papadopoulos²

2009

CPD

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The Major Histocompatibility Complex Class II locus is the primary genetic linkage to autoimmune diseases. Susceptibility to each such disease is linked to different alleles, with a few alleles showing also dominant protection. The design of vaccines for autoimmune diseases is a long sought-after goal. As knowledge about the pathogenesis of these diseases has increased, the tools for such an approach have of necessity been refined. We review below the structural essence of MHC II-linked autoimmune diseases which centers on the binding of antigenic peptides to the disease-linked MHC II proteins, and the consequent activation of cognate TCRs from pathogenic CD4+ T cells. The state of affairs in two organ-specific autoimmune diseases, type 1 diabetes, celiac disease are covered, including attempts to treat these via antigen-specific MHC II-guided measures. We offer a couple of testable suggestions as to how this approach could be improved.

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A New Twist in TCR Diversity Revealed by a Forbidden αβ TCR

Cited by 23 publications

References 45 publications

Many different Vβ CDR3s can reveal the inherent MHC reactivity of germline-encoded TCR V regions

Many different Vβ CDR3s can reveal the inherent MHC reactivity of germline-encoded TCR V regions

TCR-MHC docking orientation: natural selection, or thymic selection?

Use of MHC II Structural Features in the Design of Vaccines for Organ-Specific Autoimmune Diseases

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