Evolutionarily Conserved Features Contribute to αβ T Cell Receptor Specificity

Scott‐Browne, James; Crawford, Frances; Young, Mary; Kappler, John W.; Marrack, Philippa; Gapin, Laurent

doi:10.1016/j.immuni.2011.09.005

Cited by 59 publications

(63 citation statements)

References 73 publications

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“…Our observations would nevertheless better support the assumption that the preselected T-cell repertoire might be inherently prone to interact with MHC molecules, as proposed by various groups in the TCR/MHC coevolution theory [33,34]. The functional avidities and peptide specificities of CD8 T-cell lines derived from donors expressing or not HLA-A*0201 were also investigated.…”

Section: Quantitative Impact Of the Expression Of The Mhc Class I-ressupporting

confidence: 68%

Role of the MHC restriction during maturation of antigen‐specific human T cells in the thymus

et al. 2015

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In the thymus, a T-cell repertoire able to confer protection against infectious and noninfectious agents in a peptide-dependent, self-MHC-restricted manner is selected. Direct detection of Ag-specific thymocytes, and analysis of the impact of the expression of the MHCrestricting allele on their frequency or function has never been studied in humans because of the extremely low precursor frequency. Here, we used a tetramer-based enrichment protocol to analyze the ex vivo frequency and activation-phenotype of human thymocytes specific for self, viral and tumor-antigens presented by HLA-A*0201 (A2) in individuals expressing or not this allele. Ag-specific thymocytes were quantified within both CD4CD8 double or single-positive compartments in every donor. Our data indicate that the maturation efficiency of Ag-specific thymocytes is poorly affected by HLA-A2 expression, in terms of frequencies. Nevertheless, A2-restricted T-cell lines from A2 + donors reacted to A2 + cell lines in a highly peptide-specific fashion, whereas their alloreactive counterparts showed off-target activity. This first ex vivo analysis of human antigen-specific thymocytes at different stages of human T-cell development should open new perspectives in the understanding of the human thymic selection process. Keywords: Antigen r Human T cells r MHC r Tetramers r Thymocytes See accompanying Commentary by Ciucci and BosselutAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe thymus generates a highly diverse T-cell repertoire able to recognize virtually any antigen that could be encountered by a given individual along his/her life. This diversity is achieved through two main mechanisms. First by the acquisition by CD4 + CD8 + double-positive (DP) thymocytes of a clonally distributed T cell receptor (TCR) that is generated after somatic recombination of TCR V(D)J gene segments and nontemplated nucleotide Correspondence: Dr. Xavier Saulquin e-mail: xavier.saulquin@univ-nantes.fradditions. This quasi-random mechanism allows for the generation of up to 10 15 different receptors [1]. Second, by the shaping of this initial T-cell repertoire by positive and negative thymic selection processes that will favor emergence of a self major histocompatibility molecules (MHC)-restricted, yet self-tolerant, TCR repertoire carried by mature naïve single-positive (SP) T cells. As a consequence of this maturation process, the diversity of SP αβ T cells in a given individual falls in the range of 10 6 to 10 8 [2]. * LH and FL equally contributed to this work. The respective contributions of positive and negative thymic selection processes to the generation of a mature T-cell repertoire possibly biased towards recognition of peptides restricted by host MHC alleles are still debated. Indeed, this phenomenon referred to as "host or Self-MHC-restriction" is a consequence of a balance between (i) the need for a thymocyte to get survival signals from TCR upon interactions of weak/intermediate avidi...

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Section: Quantitative Impact Of the Expression Of The Mhc Class I-ressupporting

confidence: 68%

Role of the MHC restriction during maturation of antigen‐specific human T cells in the thymus

et al. 2015

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“…These germ-line-encoded interaction pairs include CDR2β residues Arg53 and Asn54 contacting HLA-DR residues Ala61α and Glu55α, respectively. Such interactions support the idea that coevolution of TCR and MHC molecules is a major contributor to the canonical diagonal orientation observed in TCR-pMHC complexes (2,(6)(7)(8)(9)(10)(11). However, this conserved orientation probably also reflects a role for the CD4 and CD8 coreceptors in limiting TCR-docking options on pMHC during T-cell selection (8,(11)(12)(13)(14)(15)(16)(17).…”

Section: Discussionsupporting

confidence: 68%

“…Although we have focused here on the flexibility of some germ-line-encoded interactions between TCR and MHC, it is important to emphasize that other germ-line-encoded interactions are maintained in the G4-mutTPI-DR1 and E8-mutTPI-DR1 complexes, in agreement with the TCR-MHC coevolution hypothesis (2,(6)(7)(8)(9)(10)(11). In particular, CDR2α makes nearly identical contacts with MHC in the two complexes ( Table 2).…”

Section: Discussionsupporting

confidence: 54%

“…This pairwise interaction motif comprises TCR residues CDR1β Asn31, CDR2β Tyr48, and CDR2β Glu54 contacting I-A residues Gln61α, Gln57α, and Lys39α, respectively. These and related findings demonstrating conserved interactions between germ-line-encoded CDR1 and CDR2 loops and particular MHC alleles strongly support the hypothesis that the canonical diagonal docking orientation of TCR on MHC observed in TCR-pMHC complexes is the result, at least in part, of coevolution of TCR and MHC molecules (2,(6)(7)(8)(9)(10)(11). This conserved orientation probably also reflects the requirement to form a TCR-pMHC-CD4 or TCR-pMHC-CD8 ternary complex with the CD4 or CD8 coreceptor that is geometrically competent to deliver a maturation signal to double-positive thymocytes during T-cell selection (8,(11)(12)(13)(14)(15)(16)(17).…”

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confidence: 70%

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Structural insights into the editing of germ-line–encoded interactions between T-cell receptor and MHC class II by Vα CDR3

Deng

Langley

Wang

et al. 2012

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

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The conserved diagonal docking mode observed in structures of Tcell receptors (TCRs) bound to peptide-MHC ligands is believed to reflect coevolution of TCR and MHC genes. This coevolution is supported by the conservation of certain interactions between the germ-line-encoded complementarity-determining region (CDR)1 and CDR2 loops of TCR and MHC. However, the rules governing these interactions are not straightforward, even when the same variable (V) region recognizes the same MHC molecule. Here, we demonstrate that the somatically generated CDR3 loops can markedly alter evolutionarily selected contacts between TCR and MHC ("CDR3 editing"). To understand CDR3 editing at the atomic level, we determined the structure of a human melanoma-specific TCR (G4) bound to the MHC class II molecule HLA-DR1 and an epitope from mutant triose phosphate isomerase (mutTPI). A comparison of the G4-mutTPI-DR1 complex with a complex involving a TCR (E8) that uses the same Vα region to recognize the same mutTPI-DR1 ligand as G4 revealed that CDR1α adopts markedly different conformations in the two TCRs, resulting in an almost entirely different set of contacts with MHC. Based on the structures of unbound G4 and E8, the distinct conformations of CDR1α in these TCRs are not induced by binding to mutTPI-DR1 but result from differences in the length and sequence of CDR3α that are transmitted to CDR1α. The editing of germ-line-encoded TCR-MHC interactions by CDR3 demonstrates that these interactions possess sufficient intrinsic flexibility to accommodate large structural variations in CDR3 and, consequently, in the TCR-binding site.T -cell receptors (TCRs) bind peptide-MHC (pMHC) via their six complementarity-determining region (CDR) loops, three from the variable alpha (Vα) domain and three from Vβ. The first and second CDRs (CDR1 and CDR2) are encoded within the TCR Vα and Vβ gene segments; the third CDR (CDR3) is formed by DNA recombination involving juxtaposition of Vα and Jα segments for the α chain genes, and of Vβ, D, and Jβ segments for the β chain genes. As a result, the somatically generated Vα and Vβ CDR3 loops account for most of the variability of TCRbinding sites, whereas variability contributed by CDR1 and CDR2 is restricted to that already existing in the germ line.Structural studies of numerous (>25) TCR-pMHC complexes have demonstrated remarkable similarities in the overall topology of TCR binding, irrespective of MHC class I or class II restriction (1-3). Typically, the TCR is positioned diagonally over the center of the composite surface created by the peptide and the MHC α-helices that flank the peptide-binding groove, with the Vα domain situated over the N-terminal half of the peptide and the Vβ domain over the C-terminal half, although the exact angle and pitch of TCR engagement vary (1). In addition, these studies revealed the conservation of specific TCR-MHC interactions in complexes involving common V segments and MHC alleles (2, 4-6). For example, crystal structures of six mouse TCRs expressing Vβ8.2 bound to I-A...

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“…weak sequence homology, substitution of fish V segments for the mouse V segments preserves antigen recognition of the mouse peptide-MHC complex (23). Finally, although RAG-mediated rearrangement makes the CDR3 more diverse, the CDR1 and CDR2 loops in TCRs, unlike those in Igs, do not undergo antigen-selected somatic mutation; thus they keep their germ-line sequence and antigen-driven responses throughout development, suggesting a conserved function (24,25).…”

Section: Significancementioning

confidence: 99%

Class II major histocompatibility complex mutant mice to study the germ-line bias of T-cell antigen receptors

Silberman

Krovi

Tuttle

et al. 2016

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

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The interaction of αβ T-cell antigen receptors (TCRs) with peptides bound to MHC molecules lies at the center of adaptive immunity. Whether TCRs have evolved to react with MHC or, instead, processes in the thymus involving coreceptors and other molecules select MHC-specific TCRs de novo from a random repertoire is a longstanding immunological question. Here, using nuclease-targeted mutagenesis, we address this question in vivo by generating three independent lines of knockin mice with single-amino acid mutations of conserved class II MHC amino acids that often are involved in interactions with the germ-line-encoded portions of TCRs. Although the TCR repertoire generated in these mutants is similar in size and diversity to that in WT mice, the evolutionary bias of TCRs for MHC is suggested by a shift and preferential use of some TCR subfamilies over others in mice expressing the mutant class II MHCs. Furthermore, T cells educated on these mutant MHC molecules are alloreactive to each other and to WT cells, and vice versa, suggesting strong functional differences among these repertoires. Taken together, these results highlight both the flexibility of thymic selection and the evolutionary bias of TCRs for MHC.T he genes for immunoglobulins (Igs), αβ T-cell receptors (TCRs), and antigen-presenting MHC proteins appeared at least 450 million years ago in the cartilaginous fish and are present in all modern vertebrates (1-3). The more primitive hagfish and lampreys lack these genes and have an adaptive immune system comprised of unrelated proteins (4). The main ligands for αβ TCRs are short peptides derived from self and foreign proteins, captured in a specialized groove of MHC class I (MHCI) and class II (MHCII) molecules and presented to T cells (5, 6). Functional Igs and TCRs are created by very similar recombination mechanisms involving fusion of V, J, and sometimes D gene segments with additional variations at the junctions to create an enormous potential repertoire of Igs and TCRs, suggesting a common, unknown evolutionary origin for these loci.These observations have raised several unanswered questions. For example,why did a separate TCR-rearranging gene system develop for lymphocytes recognizing peptide-MHC ligands? How did the extraordinarily polymorphic MHC genes stay functionally connected to TCR genes throughout 450 million years of evolution? One long-standing hypothesis has been that certain features of TCRs and MHC molecules are evolutionarily conserved to promote their interaction (7-10). Like Igs, the antigen-recognition portions of TCRs are partially encoded in the complementary determining region (CDR) CDR1 and CDR2 loops of germ-line TCR Vα (TRAV) and Vβ (TRBV) genes and are partially generated by somatic recombination processes that form the CDR3 loops. This initial repertoire is culled dramatically during T-cell development in the thymus. First, only those T cells whose TCRs have at least some minimal affinity for the selfpeptide-MHC molecules expressed in the thymus are positively selected for fu...

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Evolutionarily Conserved Features Contribute to αβ T Cell Receptor Specificity

Cited by 59 publications

References 73 publications

Role of the MHC restriction during maturation of antigen‐specific human T cells in the thymus

Role of the MHC restriction during maturation of antigen‐specific human T cells in the thymus

Structural insights into the editing of germ-line–encoded interactions between T-cell receptor and MHC class II by Vα CDR3

Class II major histocompatibility complex mutant mice to study the germ-line bias of T-cell antigen receptors

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