Avidity for antigen shapes clonal dominance in CD8+ T cell populations specific for persistent DNA viruses.
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.
Price
David A
DA
Human Immunology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Brenchley
Jason M
JM
Ruff
Laura E
LE
Betts
Michael R
MR
Hill
Brenna J
BJ
Roederer
Mario
M
Koup
Richard A
RA
Migueles
Steven A
SA
Gostick
Emma
E
Wooldridge
Linda
L
Sewell
Andrew K
AK
Connors
Mark
M
Douek
Daniel C
DC
D000595:Amino Acid Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000821:virology; D002478:Cells, Cultured; D002999:Clone Cells; D003587:Cytomegalovirus / Q000276:immunology; D004267:DNA Viruses / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism* / Q000502:physiology; D004854:Herpesvirus 4, Human / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D016056:Immunodominant Epitopes / Q000378:metabolism* / Q000502:physiology; D016130:Immunophenotyping; D008969:Molecular Sequence Data; D017354:Point Mutation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism*; D017735:Virus Latency / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D016056:Immunodominant Epitopes; D011948:Receptors, Antigen, T-Cell