Evaluation of immunotherapeutic effects of IL-7 during acute and chronic viral infections.

摘要

CD8+ T cells are essential for protection against viral and intracellular bacterial/protozoan infections. Development of vaccines that induce potent CD8+ T cell responses been a formidable task for immunologists. The cytokine, Interleukin-7 plays a non-redundant role in maintenance of T cell homeostasis. Although, IL-7 is known to enhance T cell immunity, the timing of therapy or its effect on T cell responses are not clearly defined. Using the mouse model of viral infections or DNA vaccine, I have investigated the effects of IL-7 therapy during different phases of T cell responses on CD8+ and CD4+ T cell memory. First, I showed that IL-7 therapy restricted to contraction phase of CD8 + T cell responses substantially enhanced the memory CD8+ T cells. Further, I demonstrated that IL-7 therapy enhanced CD8+ T cell responses primarily by inducing cellular proliferation ant not by suppressing apoptosis. In addition, I showed that IL-7 administration following DNA vaccination not only improved CD8+ T cell memory but also augmented protective immunity against a persistent viral infection. Furthermore, I found that IL-7 administration during the memory phase of CD8+ T cell response markedly augmented the memory cells albeit for a short time. Second in specific aim 2, I documented that IL-7 treatment during the expansion phase did not increase the clonal burst size or the magnitude of memory CD4+ T cell response. Further, I found that IL-7 administration during the contraction phase substantially enhanced long-term CD4+ T cell memory.;Finally, in specific aim 3, I evaluated the immunotherapeutic benefits of IL-7 on CD8+ and CD4+ T cell responses during a chronic LCMV infection. My studies revealed that effects of IL-7 on T cell responses were inversely correlated to viral load at the time of therapy. Although IL-7 therapy improved anti-viral CD8+ and CD4 + T cell responses with decreasing viral load, it did not improve viral control. In summary, my studies have implications in using IL-7 as an adjuvant to enhance the T cell responses to viral infections or vaccinations in humans.