Concomitant induction of CD4+ and CD8+ T cell responses in volunteers immunized with Salmonella enterica serovar typhi strain CVD 908-htrA. developing world, infecting over 26 million people annually (1). serovars can also cause gastroenteritis and invasive nontyphoidal salmonellosis (NTS), a systemic disease prevalent in sub-Saharan Africa (1,C3). Although there are vaccines available for treatment of infections by Typhi, none are currently available for other serovars, including Typhimurium (4, 5). Since Typhi replicates only in a human host, it has been difficult to model this disease Typhimurium infection of inbred mice is widely used as a model of systemic typhoidal and nontyphoidal disease (6, 7). Mouse models have uncovered several mechanisms by which spp. are able to invade and disseminate within the infected host. Graveoline The bacteria initially exploit intestinal epithelial M cells to gain entry into Peyers patches, where they subsequently infect dendritic cells and macrophages (8, 9), before migrating to the mesenteric lymph node and blood via the lymphatic system (10). Under some circumstances, spp. also infect lamina propria phagocytes that directly sample intestinal contents (11,C13) or breach the epithelial barrier by disrupting tight junctions (14). Once infection is initiated in the intestine, it rapidly spreads to systemic tissues, where replicates in the liver, spleen, and bone marrow (10). Host innate and adaptive immune responses are initiated rapidly after infection (15, 16). The major mechanism of bacterial killing during systemic salmonellosis is via the activation of macrophages by Th1 cell-secreted gamma interferon (IFN-) (17,C19). Mice lacking CD4 T cells demonstrated delayed bacterial clearance and had higher bacterial burdens after a month of infection (14, 20). Data from human studies support a strong association between individual resistance to enteric fever and allelic variation within the HLA class II HLA-DRB1 gene (21). On the basis of these observations in both mice and humans, the relationships among major histocompatibility complex (MHC) class II gene variation, CD4 T cell activation, and mouse resistance to IKK-gamma (phospho-Ser85) antibody infection deserve further investigation. There are several different models for studying infection in mice. Some laboratories choose to infect resistant mouse strains, while others predominantly use susceptible mouse strains that lack the protective SLC11A1 gene (22). Infection of susceptible C57BL/6 mice with an attenuated strain of Typhimurium elicits robust CD4 T cell responses that contribute to bacterial clearance (20, 23, 24). In contrast, infecting resistant mouse strains with virulent typically elicits strong antibody-mediated protection (25, 26). Despite robust expansion of CD4 T cells during infection, depleting CD4 T cells increases bacterial replication only modestly (by around 1 to 2 2 log) (20), suggesting that other protective mechanisms are important. Previous work has shown that different mouse strains eliminate Typhiumurium at vastly different rates, with C57BL/6 mice among the slowest to eradicate bacteria (27). MHC alleles themselves are influential in determining how quickly congenic mice can eradicate infection (27). On the basis of these historical data, we hypothesized that the I-Ab molecule Graveoline was particularly poor Graveoline at initiating protective CD4 T cell responses and that stronger protective CD4 T cell responses would develop in C57BL/6 mice expressing other MHC haplotypes. The present study therefore examined whether H-2 congenic mouse strains with enhanced resistance to infection elicited superior CD4 T cell-dependent protective responses. Surprisingly, our results show that, although CD4 T cells contribute to anti-immunity in different MHC congenic strains, CD8 T cells are essential to the enhanced protection evident in comparisons between strains. RESULTS Congenic mice expressing H-2k and H-2u molecules demonstrated rapid clearance of Typhimurium. We initially examined whether MHC congenic mice displayed different Graveoline rates of clearance, as had been previously reported (27). Mice possessing variant H-2 molecules at the class I and class II alleles, as well as congenic control strains, were infected intravenously with 5??105 CFU of Typhimurium, and bacterial burdens were assessed over the course of 28?days. Mice were infected intravenously because NTS is a systemic disease that is not typically associated with high bacterial burdens in the gut lamina propria (10). No significant differences were observed in the rates of bacterial clearance from the.