Avidity for antigen shapes clonal dominance in CD8+ T cell populations specific for persistent DNA viruses

Price, David ORCID: https://orcid.org/0000-0001-9416-2737, Brenchley, Jason M., Ruff, Laura E., Betts, Michael R., Hill, Brenna J., Roederer, Mario, Koup, Richard A., Migueles, Steven A., Gostick, Emma, Wooldridge, Linda, Sewell, Andrew ORCID: https://orcid.org/0000-0003-3194-3135, Connors, Mark and Douek, Daniel C. 2005. Avidity for antigen shapes clonal dominance in CD8+ T cell populations specific for persistent DNA viruses. Journal of Experimental Medicine 202 (10) , pp. 1349-61. 10.1084/jem.20051357

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Abstract

The forces that govern clonal selection during the genesis and maintenance of specific T cell responses are complex, but amenable to decryption by interrogation of constituent clonotypes within the antigen-experienced T cell pools. Here, we used point-mutated peptide–major histocompatibility complex class I (pMHCI) antigens, unbiased TCRB gene usage analysis, and polychromatic flow cytometry to probe directly ex vivo the clonal architecture of antigen-specific CD8+ T cell populations under conditions of persistent exposure to structurally stable virus-derived epitopes. During chronic infection with cytomegalovirus and Epstein-Barr virus, CD8+ T cell responses to immunodominant viral antigens were oligoclonal, highly skewed, and exhibited diverse clonotypic configurations; TCRB CDR3 sequence analysis indicated positive selection at the protein level. Dominant clonotypes demonstrated high intrinsic antigen avidity, defined strictly as a physical parameter, and were preferentially driven toward terminal differentiation in phenotypically heterogeneous populations. In contrast, subdominant clonotypes were characterized by lower intrinsic avidities and proportionately greater dependency on the pMHCI–CD8 interaction for antigen uptake and functional sensitivity. These findings provide evidence that interclonal competition for antigen operates in human T cell populations, while preferential CD8 coreceptor compensation mitigates this process to maintain clonotypic diversity. Vaccine strategies that reconstruct these biological processes could generate T cell populations that mediate optimal delivery of antiviral effector function.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > R Medicine (General)
Additional Information:	Publisher’s copyright requirements: “Ownership of copyright in the Work remains with the authors. The Authors retain the non-exclusive right to do anything they want with the Work, so long as the Authors provide attribution to the place of original publication. The retained right specifically includes the right to post the Work on the authors’ or their institutions’ web sites.” See: http://www.rupress.org/site/subscriptions/terms.xhtml
Publisher:	Rockefeller University Press
ISSN:	15409538
Last Modified:	06 May 2023 21:06
URI:	https://orca.cardiff.ac.uk/id/eprint/364

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