Contribution of Herpesvirus Specific CD8 T Cells to Anti-Viral T Cell Response in Humans

Abstract

Herpesviruses infect most humans. Their infections can be associated with pathological conditions and significant changes in T cell repertoire but evidences of symbiotic effects of herpesvirus latency have never been demonstrated. We tested the hypothesis that HCMV and EBV-specific CD8 T cells contribute to the heterologous anti-viral immune response. Volume of activated/proliferating virus-specific and total CD8 T cells was evaluated in 50 patients with acute viral infections: 20 with HBV, 12 with Dengue, 12 with Influenza, 3 with Adenovirus infection and 3 with fevers of unknown etiology. Virus-specific (EBV, HCMV, Influenza) pentamer+ and total CD8 T cells were analyzed for activation (CD38/HLA-DR), proliferation (Ki-67/Bcl-2_low) and cytokine production. We observed that all acute viral infections trigger an expansion of activated/proliferating CD8 T cells, which differs in size depending on the infection but is invariably inflated by CD8 T cells specific for persistent herpesviruses (HCMV/EBV). CD8 T cells specific for other non-related non persistent viral infection (i.e. Influenza) were not activated. IL-15, which is produced during acute viral infections, is the likely contributing mechanism driving the selective activation of herpesvirus specific CD8 T cells. In addition we were able to show that herpesvirus specific CD8 T cells displayed an increased ability to produce the anti-viral cytokine interferon-γ during the acute phase of heterologous viral infection. Taken together, these data demonstrated that activated herpesvirus specific CD8 T cells inflate the activated/proliferating CD8 T cells population present during acute viral infections in human and can contribute to the heterologous anti-viral T cell response. The majority of humans are infected by herpesviruses, such as Epstein-Barr virus and Human Cytomegalovirus, which rarely cause severe pathology but heavily distort the human T cell repertoire. Up to 20% of cytotoxic T cells can be specific to Epstein-Barr and Cytomegalovirus. It is believed that all these herpesvirus specific T cells are needed to control the persistent infection. However, it has not been explored whether these T cells can contribute to the immune response to a new viral infection. To investigate this possibility, we analyzed the volume of activated virus-specific and total T cells in patients with acute hepatitis B, dengue, influenza and adenovirus infections. We observed that all acute viral infections trigger an expansion of activated T cell population, part of which is specific to infecting agent, and the other part to herpesviruses. Our study provides evidence that persistent herpesvirus infections alter the composition of the T cell population which is activated during new acute viral infection.