The generation and maintenance of CD4+ T cell responses in concomitant immunity to Leishmania major

Infection with the intracellular protozoan parasite Leishmania major induces a state of concomitant immunity wherein secondary immunity is dependent upon the persistence of the original pathogen. Our lab has described two populations of Leishmania-induced CD4+ T cells that contribute to immunity: CD62Lhigh central memory T cells and CD62Llow effector T cells. While CD62L downregulation indicates an activated phenotype, a subset of the effector cells has further differentiated into IFN-γ-producing Th1 effector cells. The factors that result in the generation and maintenance of these populations remain largely unknown during the course of a primary L. major infection. In this thesis, we further examine these populations of CD4+ T cells whose combined efforts mediate rapid protective immunity against secondary L. major challenge. We used the adoptive transfer of CFSE-labeled transgenic and polyclonal CD4+ T cells to assay the phenotype and function of cells that proliferate in response to L. major infection, and we establish that heterogeneity within the pool of antigen-specific CD4+ T cells arises early following infection. One of the populations generated at this time had the phenotypic and functional characteristics of central memory T cells. In addition, we demonstrate that the priming of these cells occurs in the draining lymph node in the first 3 days following infection and involves and proliferative arrest of the central memory-like population. In addition, we address a potential mechanism by which Leishmania-specific CD4+ T cells are maintained following infection. The receptor for the prosurvival cytokine interleukin-7 (IL7R) was expressed at elevated levels on central memory T cells and also a population of Th1-polarized effector T cells suggesting that neither the presence of L. major parasites nor the upregulation of Th1-associated genes prevented the ability of CD4+ T cells to express the IL7R. Moreover, we demonstrate that the rapid effector response to secondary challenge is diminished when IL7R signaling is blocked suggesting a dependence upon IL-7 for the optimal function of Th1 effector cells. Collectively, the work within this thesis has provided new insights on the early CD4 + T cell response to L. major and the cells that ultimately mediate protective immunity