The roles of IL-12 and IL-23 in the Innate and Adaptive Immune Responses against Salmonella

Thesis (Ph.D.)--University of Washington, 2012→Non-typhoidal Salmonella is a major health concern worldwide typically causing gastroenteritis in people of all ages and severe invasive disease in immune-compromised persons in particular in individuals with genetic defects in innate immune signaling molecules Interleukin (IL)-12/IL-23. The innate immune system is pivotal for early control of Salmonella and proper induction of the adaptive immune system responsible for eradication of and future protection from this pathogen. IL-12 and IL-23 are important innate signaling molecules that typically work through the promotion of their downstream target Interferon (IFN)-γ and IL-17/-22, respectively. Our overall goal is to better define the roles of these cytokines using of the streptomycin pretreatment model of Salmonella -induced enterocolitis in order to develop/modify different modalities and therapies for this disease. →In the acute phase, we found that IL-23 alone was dispensable for protection against systemic spread of bacteria, but synergized with IL-12 for optimal protection. We also found that IL-12 promoted the production of IFN-γ by NK cells, which as mentioned above, is required for resistance against Salmonella and also for induction of intestinal inflammation and epithelial injury. In contrast, IL-23 controlled the severity of inflammation by inhibiting IL-12A expression, thereby reducing IFN-γ and prevented excessive mucosal injury. →In late phase studies our data showed that the combined loss of IL-12/-23 led to defective control of oral attenuated Salmonella infection, diminished the generation of antigen-specific CD4 T cells, but robust antigen specific antibody responses. IFN-γ -/- mice had a survival disadvantage compared to IL-12/-23 DKO mice. This differential survival may reflect the unexpected production of IFN-γ by IL-12/23 DKO T-cells. Surprisingly, antigen-specific Th1 cells were readily detected upon rechallenge of immunized IL-12/23 deficient mice, indicating that these cytokines are not required for the generation of Th1 cells. Nevertheless, the IL-12/23-independent, antigen-specific Th1 and antibody responses were insufficient for optimal control of late phase Salmonella infection. Together these data demonstrate the critical and complex relationship of IL-12 and IL-23 that are essential for early and late phase immunity against Salmonella