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

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.

• Authors: David A 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 K Sewell, Mark Connors, Daniel C Douek
• Journal: The Journal of experimental medicine (J Exp Med) Vol. 202 Issue 10 Pg. 1349-61 (Nov 21 2005) ISSN: 0022-1007 [Print] United States
• PMID: 16287711 (Publication Type: Journal Article)

Chemical References

• Epitopes, T-Lymphocyte
• Histocompatibility Antigens Class I
• Immunodominant Epitopes
• Receptors, Antigen, T-Cell

Topics

• Amino Acid Sequence
• CD8-Positive T-Lymphocytes (immunology, metabolism, virology)
• Cells, Cultured
• Clone Cells
• Cytomegalovirus (immunology)
• DNA Viruses (immunology)
• Epitopes, T-Lymphocyte (metabolism, physiology)
• Herpesvirus 4, Human (immunology)
• Histocompatibility Antigens Class I (genetics, immunology, metabolism)
• Humans
• Immunodominant Epitopes (metabolism, physiology)
• Immunophenotyping
• Molecular Sequence Data
• Point Mutation
• Receptors, Antigen, T-Cell (immunology)
• Reverse Transcriptase Polymerase Chain Reaction
• T-Lymphocyte Subsets (immunology, metabolism)
• Virus Latency (immunology)