CD4+-T-Cell Effector Functions and Costimulatory Requirements Essential for Surviving Mucosal Infection withCitrobacter rodentium

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Abstract
Citrobacter rodentium causes an attaching and effacing infection of the mouse colon. Surprisingly, protective adaptive immunity against this mucosal pathogen requires a systemic T-cell-dependent antibody response. To define CD4+ T-cell effector functions promoting this systemic defense of infected epithelial surfaces, studies were undertaken in weaning-age mice lacking costimulatory molecules CD28 or CD40L or cytokines gamma interferon (IFN-γ) or interleukin-4 (IL-4). Adoptive transfer of CD4+ T cells from wild-type, CD28−/−, CD40L−/−, or IFN-γ−/− donors to CD4−/− recipients delineated functions of these CD4+ T-cell-expressed molecules on the outcome of infection. Wild-type and IL-4−/− mice successfully resolved infection, while 70% of IFN-γ−/− mice survived. In contrast, all CD28−/− mice succumbed during acute infection. While fewer than half of CD40L−/− mice succumbed acutely, surviving mice failed to clear infection, resulting in progressive mucosal destruction, polymicrobial sepsis, and death 1 to 2 weeks later than in CD28−/− mice. Downstream of CD28-mediated effects, CD4+ T-cell-expressed CD40L proved essential for generating acute pathogen-specific immunoglobulin M (IgM) and early IgG, which reduced pathogen burdens. However, deficiency of CD4+ T-cell-expressed IFN-γ did not adversely impact survival or development of protective antibody in adoptively transferred CD4−/− recipients, though it impacted Th1 antibody responses. These findings demonstrate that CD4+ T-cell-expressed CD40L promotes the rapid production of protective systemic antibody during acute infection, while deficiencies of IL-4 or of CD4+ T-cell-expressed IFN-γ can be overcome. These findings have important implications for understanding the role of T-helper-cell responses during infections involving mucosal surfaces.