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Investigating Structural Drivers of Antigen Specificity
Author(s) -
Singh Nishant K,
Smith Sheena,
Harris Dan,
Kranz David,
Baker Brian M
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.937.3
Subject(s) - t cell receptor , major histocompatibility complex , human leukocyte antigen , biology , antigen , immune system , computational biology , t cell , microbiology and biotechnology , immunology
Cellular immunity and new immunotherapeutic approaches rely on interactions between T‐cell receptors (TCRs) and the peptide‐major histocompatibility complex (pMHC) to initiate successful immune responses. Achieving peptide specificity by the TCR while simultaneously engaging the pMHC is critical for proper recognition and T‐cell activation. Although early studies emphasized the role of CDR3α and CDR3β loops in determining antigen specificity, more recent work has shown that antigen specificity arises from a cooperative interplay between germline and hypervariable loops and the pMHC surface. To better understand the determinants of TCR specificity, we have been studying engineered variants of the human TCR A6, which recognizes the viral peptide Tax presented by the class I MHC HLA‐A2, but has also been re‐engineered to recognize the tumor associated antigen MART‐1 with high specificity. An additional variant shows a surprising loss of specificity, recognizing a large range of structurally and chemically distinct peptide/HLA‐A2 complexes with high affinity. Here, we describe the structural and biochemical features that correlate with this loss in specificity and discuss the implications for how TCRs achieve specificity and how it can be manipulated.