IFN-Gamma-Dependent and Independent Mechanisms of CD4+ Memory T Cell-Mediated Protection from Listeria Infection

While CD8(+) memory T cells can promote long-lived protection from secondary exposure to intracellular pathogens, less is known regarding the direct protective mechanisms of CD4(+) T cells. We utilized a prime/boost model in which mice are initially exposed to an acutely infecting strain of lymphocytic choriomeningitis virus (LCMV), followed by a heterologous rechallenge with Listeria monocytogenes recombinantly expressing the MHC Class II-restricted LCMV epitope, GP(61-80) (Lm-gp6l). We found that heterologous Lm-gp6l rechallenge resulted in robust activation of CD4(+) memory T cells and that they were required for rapid bacterial clearance. We further assessed the relative roles of TNF and IFN gamma in the direct anti-bacterial function of CD4(+) memory T cells. We found that disruption of TNF resulted in a complete loss of protection mediated by CD4(+) memory T cells, whereas disruption of IFN gamma signaling to macrophages results in only a partial loss of protection. The protective effect mediated by CD4(+) T cells corresponded to the rapid accumulation of pro-inflammatory macrophages in the spleen and an altered inflammatory environment in vivo. Overall, we conclude that protection mediated by CD4(+) memory T cells from heterologous Listeria challenge is most directly dependent on TNF, whereas IFN gamma only plays a minor role.