Price, D.A. et al. Avidity for antigen shapes clonal dominance in CD8+ T cell populations specific for persistent DNA viruses. J. Exp. Med. 202, 1349-1361

Human Immunology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Journal of Experimental Medicine (Impact Factor: 12.52). 12/2005; 202(10):1349-61. DOI: 10.1084/jem.20051357
Source: PubMed


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.

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Article: Price, D.A. et al. Avidity for antigen shapes clonal dominance in CD8+ T cell populations specific for persistent DNA viruses. J. Exp. Med. 202, 1349-1361

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    • "Fluorochrome-conjugated ELA/HLA-A2 tetramers were produced and used as described previously (Price et al., 2005). The D227K/T228A compound mutation was introduced into the a3 domain of HLA-A2 to generate CD8-null tetramers, which enable the selective identification of high-avidity antigen-specific CD8 + T-cells (Purbhoo et al., 2001; Wooldridge et al., 2009). "
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    • "In this regard, the T cell receptor (TCR) is an excellent marker that allows antigen-specific responses to be followed along T cell differentiation and over time [11]. Thorough analyses of both viral and tumor antigen-specific CD8 T cell responses have revealed that the antigen-specific T cell repertoire is generally composed of highly frequent (also defined as dominant) as well as less frequent (defined as non-dominant) T cell clonotypes [12,13]. Through a process known as TCR clonotype selection, certain clonotypes may become more dominant along T cell differentiation [14-16] or throughout the time course of infection [17]. "
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    • "Polyclonal αPD-1–biotin was obtained from R&D Systems. The fluorescent-peptide–Mamu-A*01 tetrameric complexes central memory 9 (CM9)-PE (Gag, CTPYDINQM; residues 181 to 189) and TL8-PE (Tat, TTPESANL; residues 28 to 35) were produced in house, as described previously (19). "
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