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. 2005 Dec 15;175(12):8218-25.
doi: 10.4049/jimmunol.175.12.8218.

Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion

Jean M Fletcher  1 , Milica Vukmanovic-Stejic, Padraic J Dunne, Katie E Birch, Joanne E Cook, Sarah E Jackson, Mike Salmon, Malcolm H Rustin, Arne N Akbar
Affiliations

Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion

Jean M Fletcher et al. J Immunol. .

Abstract

Repeated antigenic encounter drives proliferation and differentiation of memory T cell pools. An important question is whether certain specific T cells may be driven eventually to exhaustion in elderly individuals since the human life expectancy is increasing. We found that CMV-specific CD4+ T cells were significantly expanded in healthy young and old carriers compared with purified protein derivative-, varicella zoster virus-, EBV-, and HSV-specific populations. These CMV-specific CD4+ T cells exhibited a late differentiated phenotype since they were largely CD27 and CD28 negative and had shorter telomeres. Interestingly, in elderly CMV-seropositive subjects, CD4+ T cells of different specificities were significantly more differentiated than the same cells in CMV-seronegative individuals. This suggested the involvement of bystander-secreted, differentiation-inducing factors during CMV infection. One candidate was IFN-alpha, which induced loss of costimulatory receptors and inhibited telomerase in activated CD4+ T cells and was secreted at high levels by CMV-stimulated plasmacytoid dendritic cells (PDC). The CMV-specific CD4+ T cells in elderly subjects had severely restricted replicative capacity. This is the first description of a human memory T cell population that is susceptible to being lost through end-stage differentiation due to the combined effects of lifelong virus reactivation in the presence of bystander differentiation-inducing factors.

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