Title

The CD4+ T cell response to Salmonella infection

Date of Completion

January 2007

Keywords

Health Sciences, Immunology

Degree

Ph.D.

Abstract

Salmonella typhi is the causative organism for typhoid fever, a serious systemic disease in humans. Immune responses to typhoid fever have been studied in murine typhoid, a disease in mice analogous to typhoid fever, which is caused by Salmonella typhimurium. CD4 + T cells have long been known to be critical for immunity against Salmonella, however, little is known about the CD4+ T cell response during infection in terms of clonal expansion, development of effector functions and trafficking. The main hurdle to understanding CD 4+ T cell function in Salmonella is the fact that in vivo antigenic targets have not been identified. To get around this, we designed an assay where in vivo restimulation with a preparation of heat-killed Salmonella typhimurium was used to detect Salmonella-specific CD4+ T cells. We found massive expansion of CD4+ T cells reaching a peak frequency of almost 50%, a clonal burst size that has never previously been observed for CD4+ T cells. We also found that a large proportion of activated CD4+ T cells during Salmonella infection acquired the ability to rapidly produce IFN-γ in response to innate stimuli, a phenomenon that has been previously described for CD 8+ T cells in infectious disease models. This innate responsiveness is partially mediated by IL-18, which is required for optimal control of infection. We also investigated the phenomenon of immunosuppression that has previously been reported to occur during Salmonella infection. We found that although CD4+ T cells are not actually suppressed in Salmonella -infected mice, they are rendered highly susceptible to suppression following administration of additional inflammatory stimulus such as LPS. This suppression occurs rapidly following exposure to the Salmonella -infected environment, and is not restricted to Salmonella -specific T-cells. Substantiating this finding, repeated exposure to low dose LPS caused uncontrolled growth of attenuated-bacteria in vivo. ^