Journal
JOURNAL OF IMMUNOLOGY
Volume 194, Issue 7, Pages 3487-3500Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.1401717
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Funding
- Takara Bio, Inc., National Institutes of Health Grant [R01 CA148673]
- Ontario Institute for Cancer Research Clinical Investigator Award [IA-039]
- Princess Margaret Cancer Foundation
- Guglietti Fellowship Award
- Knudson Postdoctoral Fellowship
- Frederick Banting and Charles Best Canada Graduate Scholarship
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TCR alpha- and beta-chains cooperatively recognize peptide -MHC complexes. It has been shown that a chain-centric TCR hemichain can, by itself, dictate MHC-restricted Ag specificity without requiring major contributions from the paired TCR counterchain. Little is known, however, regarding the relative contributions and roles of chain-centric and its counter, non chain-centric, hemichains in determining T cell avidity. We comprehensively analyzed a thymically unselected T cell repertoire generated by transducing the a-chain centric HLA-A*02:01(A2)/MART1(27-35) TCR alpha, clone SIG35 alpha, into A2-matched and unmatched post-thymic T cells. Regardless of their HLA-A2 positivity, a substantial subset of peripheral T cells transduced with SIG35 alpha gained reactivity for A2/MART1(27-35). Although the generated A2/MART1(27-35) specific T cells used various TRBV genes, TRBV27 predominated with >10(2) highly diverse and unique clonotypic CDR3 beta sequences. T cells individually reconstituted with various A2/MART1(27-35) TRBV27 TCR beta genes along with SIG35a possessed a wide range (>2 log orders) of avidity. Approximately half possessed avidity higher than T cells expressing clone DMF5, a naturally occurring A2/MART1(27-35) TCR with one of the highest affinities. Importantly, similar findings were recapitulated with other self-Ags. Our results indicate that, although a chain-centric TCR hemichain determines Ag specificity, the paired counterchain can regulate avidity over a broad range (>2 log orders) without compromising Ag specificity. TCR chain centricity can be exploited to generate a thymically unselected Ag-specific T cell repertoire, which can be used to isolate high-avidity antitumor T cells and their uniquely encoded TCRs rarely found in the periphery because of tolerance.
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