- Adoptive cell therapy with tumor-specific T cells can mediate durable cancer regression. The prime target of tumor-specific T cells are neoantigens arising from mutations in self-proteins during malignant transformation. To understand T cell recognition of cancer neoantigens at the atomic level, we studied oligoclonal T cell receptors (TCRs) that recognize a neoepitope arising from a driver mutation in the p53 oncogene (p53R175H) presented by the major histocompatibility complex class I molecule HLA-A2.
- T cells generate adaptive immune responses mediated by the T cell receptor (TCR)–CD3 complex comprising an αβ TCR heterodimer noncovalently associated with three CD3 dimers. In early T cell activation, αβ TCR engagement by peptide–major histocompatibility complex (pMHC) is first communicated to the CD3 signaling apparatus of the TCR–CD3 complex, but the underlying mechanism is incompletely understood. It is possible that pMHC binding induces allosteric changes in TCR conformation or dynamics that are then relayed to CD3.
- Influenza A virus (IAV) causes an acute infection in humans that is normally eliminated by CD8+ cytotoxic T lymphocytes. Individuals expressing the MHC class I molecule HLA-A2 produce cytotoxic T lymphocytes bearing T-cell receptors (TCRs) that recognize the immunodominant IAV epitope GILGFVFTL (GIL). Most GIL-specific TCRs utilize α/β chain pairs encoded by the TRAV27/TRBV19 gene combination to recognize this relatively featureless peptide epitope (canonical TCRs). However, ∼40% of GIL-specific TCRs express a wide variety of other TRAV/TRBV combinations (non-canonical TCRs).
- Background: The human public T cell response to a dominant CMV epitope features high clonal diversity.Results: Structures of two public TCRs bound to this CMV epitope and HLA-A2 reveal different recognition strategies.Conclusion: These structures show how the same public complementarity-determining region 3α (CDR3α) motif can associate with different variable α regions and pair with different CDR3βs.Significance: This structural interchangeability generates a clonally diverse public TCR repertoire.
- Background: Understanding T cell signaling requires knowing the structure of the TCR-CD3 complex.Results: Solution NMR was used to identify the docking site for CD3 ectodomains on the TCR β chain.Conclusion: The docking site (∼400 Å2) comprises ∼10 Cβ residues at the base of the TCR.Significance: CD3 is located opposite to the peptide-MHC binding site of the TCR.
- Background: HCV uses glycan shielding to mask epitopes recognized by neutralizing antibodies.Results: The structure of a human antibody bound to an HCV E2 epitope revealed how it penetrates a shield created by glycosylation shifting.Conclusion: Antibody binding induces an epitope conformation that accommodates multiple glycans.Significance: The structure provides a template for engineering E2 to elicit protective antibodies able to overcome glycosylation shifting.