The basis for limited specificity and MHC restriction in a T cell receptor interface

Piepenbrink, Kurt H.; Blevins, Sydney J.; Scott, Daniel R.; Baker, Brian M.

doi:10.1038/ncomms2948

Cited by 45 publications

(79 citation statements)

References 45 publications

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“…Our findings are consistent with fundamental studies on TCR recognition showing that TCR engagement of pMHC depends on unique surface chemistries provided by both the peptide and MHC, whose "roles" in binding are not easily separable (40). Our findings therefore echo suggestions that at the molecular level, TCR allorecognition is more "normal" than "abnormal" (3, 12).…”

Section: Discussionsupporting

confidence: 82%

How an alloreactive T-cell receptor achieves peptide and MHC specificity

Wang

Singh

Spear

et al. 2017

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

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T-cell receptor (TCR) allorecognition is often presumed to be relatively nonspecific, attributable to either a TCR focus on exposed major histocompatibility complex (MHC) polymorphisms or the degenerate recognition of allopeptides. However, paradoxically, alloreactivity can proceed with high peptide and MHC specificity. Although the underlying mechanisms remain unclear, the existence of highly specific alloreactive TCRs has led to their use as immunotherapeutics that can circumvent central tolerance and limit graft-versus-host disease. Here, we show how an alloreactive TCR achieves peptide and MHC specificity. The HCV1406 TCR was cloned from T cells that expanded when a hepatitis C virus (HCV)-infected HLA-A2 − individual received an HLA-A2 + liver allograft. HCV1406 was subsequently shown to recognize the HCV nonstructural protein 3 (NS3):1406-1415 epitope with high specificity when presented by HLA-A2. We show that NS3/HLA-A2 recognition by the HCV1406 TCR is critically dependent on features unique to both the allo-MHC and the NS3 epitope. We also find cooperativity between structural mimicry and a crucial peptide "hot spot" and demonstrate its role, along with the MHC, in directing the specificity of allorecognition. Our results help explain the paradox of specificity in alloreactive TCRs and have implications for their use in immunotherapy and related efforts to manipulate TCR recognition, as well as alloreactivity in general.T-cell receptor | peptide-MHC | structure | alloreactivity | specificity

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Section: Discussionsupporting

confidence: 82%

How an alloreactive T-cell receptor achieves peptide and MHC specificity

Wang

Singh

Spear

et al. 2017

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

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“…Tyr48β and Arg65 are thus clearly important for DMF5 recognition. These results are consistent with alanine mutations at these positions in other TCR-pMHC interfaces (31,40), as well as the impact of mutations to Tyr48β on T-cell development (36).…”

supporting

confidence: 78%

“…interaction we have previously studied in detail (13,40). The shape complementarity between Tyr48β and Arg65 in the DMF5 interface is high, with an interresidue Sc statistic of 0.8.…”

mentioning

confidence: 99%

“…For electrostatic interactions, the ΔG int from a double-mutant cycle reflects the interresidue coulombic interactions (28). With the A6 TCR binding Tax/A2, we previously used double-mutant cycles to measure the strength of the interaction between Arg65 and Asp99 of CDR3α (40). The experimental ΔG int was a highly favorable value of −2.8 kcal/mol.…”

mentioning

confidence: 99%

“…To assess this, we measured the interaction between the two alanine mutants, which when combined with the measurements for the wild type and two single mutants allowed us to construct a double-mutant cycle targeting the Tyr48β-Arg65 interaction. In a double-mutant cycle, the interaction free energy between two side chains (ΔG int ) is equal to the difference between the ΔΔG°of the double mutant and the sum of the ΔΔG°values of the two single mutants (40,41).…”

mentioning

confidence: 99%

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How structural adaptability exists alongside HLA-A2 bias in the human αβ TCR repertoire

Blevins

Pierce

Singh

et al. 2016

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

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How T-cell receptors (TCRs) can be intrinsically biased toward MHC proteins while simultaneously display the structural adaptability required to engage diverse ligands remains a controversial puzzle. We addressed this by examining αβ TCR sequences and structures for evidence of physicochemical compatibility with MHC proteins. We found that human TCRs are enriched in the capacity to engage a polymorphic, positively charged "hot-spot" region that is almost exclusive to the α1-helix of the common human class I MHC protein, HLA-A*0201 (HLA-A2). TCR binding necessitates hot-spot burial, yielding high energetic penalties that must be offset via complementary electrostatic interactions. Enrichment of negative charges in TCR binding loops, particularly the germ-line loops encoded by the TCR Vα and Vβ genes, provides this capacity and is correlated with restricted positioning of TCRs over HLA-A2. Notably, this enrichment is absent from antibody genes. The data suggest a built-in TCR compatibility with HLA-A2 that biases receptors toward, but does not compel, particular binding modes. Our findings provide an instructional example for how structurally pliant MHC biases can be encoded within TCRs.T-cell receptor | peptide/MHC | structure | binding | MHC bias

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T cell receptor alpha variable 12‐2 bias in the immunodominant response to Yellow fever virus

et al. 2017

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The repertoire of human αβ T‐cell receptors (TCRs) is generated via somatic recombination of germline gene segments. Despite this enormous variation, certain epitopes can be immunodominant, associated with high frequencies of antigen‐specific T cells and/or exhibit bias toward a TCR gene segment. Here, we studied the TCR repertoire of the HLA‐A*0201‐restricted epitope LLWNGPMAV (hereafter, A2/LLW) from Yellow Fever virus, which generates an immunodominant CD8+ T cell response to the highly effective YF‐17D vaccine. We discover that these A2/LLW‐specific CD8+ T cells are highly biased for the TCR α chain TRAV12‐2. This bias is already present in A2/LLW‐specific naïve T cells before vaccination with YF‐17D. Using CD8+ T cell clones, we show that TRAV12‐2 does not confer a functional advantage on a per cell basis. Molecular modeling indicated that the germline‐encoded complementarity determining region (CDR) 1α loop of TRAV12‐2 critically contributes to A2/LLW binding, in contrast to the conventional dominant dependence on somatically rearranged CDR3 loops. This germline component of antigen recognition may explain the unusually high precursor frequency, prevalence and immunodominance of T‐cell responses specific for the A2/LLW epitope.

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The basis for limited specificity and MHC restriction in a T cell receptor interface

Cited by 45 publications

References 45 publications

How an alloreactive T-cell receptor achieves peptide and MHC specificity

How an alloreactive T-cell receptor achieves peptide and MHC specificity

How structural adaptability exists alongside HLA-A2 bias in the human αβ TCR repertoire

T cell receptor alpha variable 12‐2 bias in the immunodominant response to Yellow fever virus

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