The Size and Phenotype of Virus-Specific T Cell Populations Is Determined by Repetitive Antigenic Stimulation and Environmental Cytokines

Abstract

Based on the expression of the TNFR SFP CD27, two Ag-primed CD8+ T cell subsets can be discerned in the circulation of healthy individuals: CD27+ T cells that produce a variety of cytokines but do not display immediate cytolytic activity; and cytotoxic CD27− T cells, which secrete only IFN-γ and TNF-α. The mechanism that controls the generation of these different phenotypes is unknown. We show that CMV reactivation not only increases the number of virus-specific T cells but also induces their transition from a CD27+ to a CD27− phenotype. In support of a relation between pool size and phenotype in a cohort of latently infected individuals, the number of Ag-specific CD27− CD8+ T cells was found to be linearly related to the total number of CMV-specific CD8+ T cells. In vitro studies revealed that the acquisition of the CD27− phenotype on CMV-specific T cells depended on the interaction of CD27 with its cellular ligand, CD70. Expression of CD70 was proportional to the amount of antigenic stimulation and blocked by the CD4+ T cell-derived cytokine IL-21. Thus, induction of CD70, which may vary in distinct viral infections, appears to be a key factor in determining the size and phenotype of the CMV-specific T cell population in latently infected individuals.

Differential Usage of Cellular Niches by Cytomegalovirus versus EBV- and Influenza Virus-Specific CD8+ T Cells

“…How could this affect our results? It has been described before that immunosuppressed individuals have higher percentages of CMV-specific cells and that these cells have a more differentiated phenotype (9,18,23). We believe that this can be explained by more frequent reactivations of CMV because of insufficient control by the immune system during the latency stage.…”

“…Fourth, we observed no changes in CD8 ϩ T cells recognizing other viruses upon primary CMV-infection or in CMV-seropositive individuals during the first year after transplantation. Lastly, it has been shown before that the higher the percentage of CMV-specific CD8 ϩ T cells, the more these cells have a CD27 Ϫ phenotype (23).…”

Properties of murine CD8+CD27- T cells

“…CD27 expression is down modulated after repetitive interactions with its ligand, CD70. Down modulation of CD27 of in vitro activated human CD27 + CMV-specific T cells could be blocked with anti-CD70 antibodies [27]. In CD70 transgenic mice in which all B cells express CD70, all mature peripheral T cells lack CD27 expression, whereas thymic T cells, which hardly encounter high CD70 expression, still do express CD27 [46].…”

“…CD27-deficient mice show reduced numbers of effector and memory T cells upon influenza infection [21] whereas CD70-transgenic mice showed enhanced numbers and functionally improved effector T cells after influenza or tumor challenge [20]. In vitro studies with human CMVspecific T cells showed that the antigen dose positively correlated with the CD70 expression levels that are induced [27]. Roman et al [50] showed that after influenza infection a broad spectrum of antigen-specific effector and memory CD4 + T cells emerge.…”

“…In humans, CD27 is expressed on all naive T cells and is markedly up-regulated early after activation [23,24]. However, prolonged and repetitive stimulation of CD27 by CD70 induces down-regulation of the former molecule both in vitro [25] and in vivo [26,27], suggesting that CD27 -T cells are formed as a consequence of extensive receptor triggering.…”