Skip to main content
Article thumbnail
Location of Repository

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

By David Price, Jason M. Brenchley, Laura E. Ruff, Michael R. Betts, Brenna J. Hill, Mario Roederer, Richard A. Koup, Steven A. Migueles, Emma Gostick, Linda Wooldridge, Andrew Sewell, Mark Connors and Daniel C. Douek

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

Topics: R1
Publisher: Rockefeller University Press
Year: 2005
OAI identifier: oai:http://orca.cf.ac.uk:364

Suggested articles


To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.