CD4+ T cells regulate multiple aspects of adaptive immune responses to intracellular pathogens through the secretion of pro-inflammatory cytokines. Innate cells of the immune system detect and respond to pathogens by secreting a number of innate cytokines that instruct the development of effector T cells. A key innate cytokine, IL-12, drives the development of naive CD4+ T cells to become efficient Th1 effector cells capable of secreting high levels of IFN-( and TNF-(. IFN-( and TNF-( act in concert to recruit and activate phagocytic cells and to promote the oxidative burst. In addition to IL-12, many intracellular pathogens promote the secretion of type I interferon (IFN-(/() from innate cells. However, unlike IL-12, IFN-(/( does not directly promote Th1 development in either murine or human CD4+ T cells. Rather, we have recently discovered that IFN-(/( promotes the development of a subset of human CD4+ central memory cells. This memory subset retains the capacity to secrete high levels of IL-2 and possesses the ability to generate secondary effector cells upon re-challenge with antigen. Based on these observations, we propose that IFN-(/( represents a key innate cytokine that regulates the development of CD4+ memory T cells. Further, we propose that IFN-(/(, through the induction of IL-2 in CD4+ T cells, provides help for CD8+ T cell memory development. This hypothesis will be tested with the following specific aims: 1) Determine the ability of IFN-(/( to direct memory CD4+ T cell development;2) Determine the ability of IFN-(/( to regulate CD4- dependent help for CD8 T cell memory development in vivo. The preliminary data supporting these hypotheses utilized primary human CD4+ T cells. With this proposal, we wish to determine molecular pathways that mediate IFN-a/p-dependent memory cell development. The experimental design involves the use of genetically manipulated animals in conjunction with in vivo infection models. We will test for the dependence of IFN-(/( signaling in CD4+ cells by utilizing the OT-II T cell receptor transgenic line crossed to various knock-out strains including the IFN-(/( receptor knock-out. Antigen specific resonses will be measured following infections with vesicular stomatitis virus and L. monocytogenes, both engineered to express the ovalbumin antigen. These studies will define the role of type I interferon in the generation and development of memory CD4+ T cells. While other cytokines such as IL-7 and IL-15 regulate the maintenance of memory cells, the findings from this study will significantly broaden our understading of the genesis of memory cell development and will have significant impact on the design of more safe and effective vaccines.
