IL-21 and IL-15 cytokine DNA augments HSV specific effector and memory CD8+ T cell response

The recurrence of lesions and transmission of Herpes simplex virus is dependent on the number and function of viral specific CD8+ T cells, especially the memory T cells. The generation, turnover and set point of this cell population is maintained by different factors like exposure to antigen, cytokines and co-stimulatory molecules. However, the contribution of these factors in the generation and maintenance of the memory CD8+ T cell population is still controversial, since it is not clear if homeostatic proliferation driven by cytokines can overcome T cell receptor (TCR) signaling. Since, interleukin 15 (IL-15) and interleukin 21 (IL-21) are cytokines implicated in homeostatic control of CD8+ T cell pool, we constructed and used expression plasmids coding for IL-15 (pIL-15) and IL-21 (pIL-21) to expand HSV specific CD8+ T cells in an animal model. Our results showed that the IL-21 increased the frequency of CD8+ T cells in the absence of antigen, although the magnitude of this response was dependent on TCR signaling. Both pIL-15 and pIL-21 boosted the numbers of antigen specific CD8+ IFNγ producing cells in the primary response. In the memory phase, numbers of CD8+ CD44high as well as CD8+ T cells producing IFN-γ and TNF-α were increased when pIL-15 and pIL-21 were used alone or in combination, compared to vector treatment only, and association of antigen further increased the proliferative response. Our data suggest that genetic treatment with pIL-15 and pIL-21 in the presence or absence of cognate antigen can contribute to immune-enhancement against HSV.