In Vivo Persistence of Codominant Human CD8+ T Cell Clonotypes Is Not Limited by Replicative Senescence or Functional Alteration

University of Freiburg, Freiburg, Baden-Württemberg, Germany
The Journal of Immunology (Impact Factor: 4.92). 09/2007; 179(4):2368-79. DOI: 10.4049/jimmunol.179.4.2368
Source: PubMed


T cell responses to viral epitopes are often composed of a small number of codominant clonotypes. In this study, we show that tumor Ag-specific T cells can behave similarly. In a melanoma patient with a long lasting HLA-A2/NY-ESO-1-specific T cell response, reaching 10% of circulating CD8 T cells, we identified nine codominant clonotypes characterized by individual TCRs. These clonotypes made up almost the entire pool of highly differentiated effector cells, but only a fraction of the small pool of less differentiated "memory" cells, suggesting that the latter serve to maintain effector cells. The different clonotypes displayed full effector function and expressed TCRs with similar functional avidity. Nevertheless, some clonotypes increased, whereas others declined in numbers over the observation period of 6 years. One clonotype disappeared from circulating blood, but without preceding critical telomere shortening. In turn, clonotypes with increasing frequency had accelerated telomere shortening, correlating with strong in vivo proliferation. Interestingly, the final prevalence of the different T cell clonotypes in circulation was anticipated in a metastatic lymph node withdrawn 2 years earlier, suggesting in vivo clonotype selection driven by metastases. Together, these data provide novel insight in long term in vivo persistence of T cell clonotypes associated with continued cell turnover but not replicative senescence or functional alteration.

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Available from: Yolanda D Mahnke
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    • "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]. Persistence of human virus-specific T cell clonotypes over several years has been demonstrated in humans with various viral infections: influenza [18], herpes simplex virus [19,20], EBV [21], cytomegalovirus (CMV) [14] and human immunodeficiency virus (HIV) [22]. "
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    • "In the future, comprehensive analyses of TCR repertoire and T-cell function will improve the characterization of T-cell responses. Recently, ex vivo assessment of cytokine production and cytotoxicity has become possible for groups of dominant T-cell clonotypes44 and even individual clonotypes, as we have demonstrated in a strong NY-ESO-1-specific T-cell response of a melanoma patient.17 As T-cell avidity and functionality are key for immune protection, such studies have the potential to reveal correlates of protection against disease,45 providing the rationale to improve T-cell based immunotherapies. "
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