CD4+ T cell migration during leishmaniasis: Implications for priming, effector function and memory

All stages in the lifespan of T cells—development, activation, differentiation and death—require migration to and from different anatomical locations in the body. In this thesis, we examine the relationship between CD4+ T cell migration and protective immunity during infection with the protozoan parasite, Leishmania major. First, we describe that L. major infection induces the transient expression of a specific set of chemokine genes (XCL1, CXCL10 and CCL2) in the draining lymph node of resistant mice by 16 hours post-infection. Furthermore, neutralization of IL-12 or IFN-γ in resistant mice results in decreased chemokine expression, while administration of IL-12 to susceptible mice resulted in an increase in the level of chemokine gene expression. We also show that CD62L plays a role in the priming of protective effector TH1 cells during infection. However, CD62L-dependent homing to LNs is not required for immunity to rechallenge. Next, we demonstrate that CD4+ T cells recruited to the cutaneous compartment during infection with Leishmania major express P- and E-selectin ligands (PESLs). We show that expression of PESLs correlates with activated Leishmania-specific TH1 cells and is dependent upon IL-12. Mice lacking both P- and E-selectins develop less inflammation at the site of a primary and secondary infection, exhibit an impaired delayed-type hypersensitivity response but control of parasite replication. Finally, we identify a population of central memory CD4+ T (TCM) cells that are defined primarily by their ability to home to lymph nodes. Similar to effector T (TEFF) cells, these Leishmania-specific TCM cells are antigen-experienced yet do not produce effector cytokines after restimulation. Furthermore, T CM cells are long-lived in the absence of persistent parasites and provide protection to challenge infection. In summary, this thesis identifies a critical role for molecules involved in T cell migration in the development of resistance to infection with L. major. Most importantly, based primarily on their pattern of migration, we identify a population of memory T cells that may be critical in vaccines against pathogenic organisms that require cell-mediated immunity for their control