The role of central memory CD4+ T cells in Leishmania major infection

Abstract

This thesis characterizes and explores the role of central memory CD4 + T cells generated in response to Leishmania major infection. Central memory CD4+ T (Tcm) cells provide a pool of lymph node-homing, antigen-experienced cells that are capable of responding rapidly after a secondary infection. We have previously described a population of Tcm cells in L. major infected mice that were capable of mediating immunity to a secondary infection. The first part of this thesis focuses on characterizing the Tcm cells generated in response to L. major infection. Our results suggest that this population is non-polarized and requires IL-12 in order to differentiate into Th1 effector cells. IL-12 is a heterodimeric cytokine composed of two subunits, p35 and p40. However, the p40 subunit can also associate with a distinct p19 subunit to form the cytokine IL-23. The main role of IL-23 appears to be the maintenance of Th17 effector cells. Th17 cells can increase inflammation by increasing the recruitment of immune cells to site of infection. The second part of this thesis focuses on expanding our understanding of the role of IL-23 in L. major infection. We show that IL-23 is necessary for the increased inflammation observed following high-dose L. major infection and that this inflammation is most likely being mediated by a population of IL-17 producing effector cells. In the third part of this thesis we use attenuated Ipg2- mutant parasites to examine the cell populations involved in immunity. Lpg2- mutant parasites persist in mice without inducing any overt pathology. These parasites were generated by the deletion of the LPG2 gene and as a result fail to synthesize LPG and other surface and secreted phosphoglycans and proteophosphoglycans. We have previously shown that Ipg2- mutant parasites are capable of conferring complete protection against virulent L. major challenge. The data shown here suggests that the protection induced by Ipg2- parasites is mediated in part by a population of CD4 + and CD8+ central memory T cells. The work of this thesis provides insight into the generation of central memory CD4+ T cells and their requirements for providing protection against L. major infection