T(h)17 cells represent a new pro-inflammatory T(h) cell lineage distinct from T(h)1 and T(h)2 cells. T(h)17 cells have been shown to be involved in extracellular bacterial infection but their role in intracellular infection remains unclear. We found antigen-specific IL-17A production during a systemic infection of mice with the facultative intracellular bacterium Salmonella enterica serovar Enteritidis (S. Enteritidis) and examined the function and cellular source of IL-17A during the adaptive immune response to S. Enteritidis. Infected IL-17A-/- mice survived completely after inoculation with the highest infection dose found to be sub-lethal for wild-type (WT) C57BL/6 mice. However, at 20 and 80 days post-infection (d.p.i.), we repeatedly found mildly elevated bacterial burden in spleen and liver of IL-17A-/- mice as compared with WT mice. Overall, IL-17A-/- mice showed reduced clearance of S. Enteritidis. S. Enteritidis-specific IL-17A production was induced in splenocytes and lymph node cells of infected WT mice at both time points, 20 and 80 d.p.i. Classical CD4+ T(h)17 cells developed upon infection with Salmonella. CD4- gammadelta TCR+ and CD4- gammadelta TCR- cells were found to be additional IL-17A-producing cell populations. In infected IL-17A-/- mice, a normal T(h)1 cytokine profile was observed consistent with the overall subtle phenotype. Nevertheless, in the absence of IL-17A, recruitment of neutrophils and delayed-type hypersensitivity (DTH) reactivity was significantly compromised. Our data indicate that IL-17A responses are induced by Salmonella and mildly contribute to protective immunity during S. Enteritidis infection. Thus, IL-17A complements the IL-12/IFN-gamma axis which is essential for protective immunity against salmonellosis in mice and men.

IL-12 is essential for protective T cell-mediated immunity against Salmonella infection. To characterize the role of the related cytokine IL-23, wild-type (WT) C57BL/6 and p19−/− mice were infected systemically with an attenuated strain of Salmonella enterica serovar Enteritidis (S. Enteritidis). IL-23-deficient mice controlled infection with S. Enteritidis similarly as WT mice. Similar IFN-γ production as compared with WT mice, but defective IL-17A and IL-22 production was found in the absence of IL-23. Nevertheless, although IL-23 is required for T cell-dependent cytokine responses, IL-23 is dispensable for protection against S. Enteritidis when IL-12 is present. To analyze the role of IL-23 in the absence of IL-12, low doses of S. Enteritidis were administered to p35−/− mice (lacking IL-12), p35/19−/− mice (lacking IL-12 and IL-23), p35/40−/− mice (lacking IL-12, IL-23, and homodimeric IL-12p40), or p35/IL-17A−/− mice (lacking IL-12 and IL-17A). We found survival of p35−/− and p35/IL-17A−/− mice, whereas p35/19−/− and p35/40−/− mice died within 3–6 wk and developed liver necrosis. This indicates that IL-23, but not homodimeric IL-12p40, is required for protection, which, surprisingly, is independent of IL-17A. Moreover, protection was associated with IL-22, but not IL-17F or IL-21 expression or with neutrophil recruitment. Finally, anti-IL-22 treatment of S. Enteritidis-infected p35−/− mice resulted in liver necrosis, indicating a central role of IL-22 in hepatocyte protection during salmonellosis. In conclusion, IL-23-dependent IL-22, but not IL-17 production is associated with protection against systemic infection with S. Enteritidis in the absence of IL-12.

Early activation of the IL-12/IFN-gamma axis has been shown following Salmonella enterica serovar Enteritidis (S. Enteritidis) infection. We were interested to study whether IL-22 and IL-17A production is initiated early in response to S. Enteritidis. We demonstrate here that IL-22 was strongly elevated in the peritoneal lavage fluid and in serum already 1 day post-intraperitoneal infection (d.p.i.) of mice; not only IL-22 but also IL-17A was produced ex vivo by activated peritoneal exudate cells (PEC). Peritoneal gammadelta T cells were identified as cellular source of IL-17A. The early IL-22 production was completely IL-23-dependent. In contrast, IL-17A production was only partially IL-23-dependent. To investigate the local production of upstream cytokines important for induction of IL-22, IL-17A and IFN-gamma during salmonellosis, the production of IL-23 and IL-12 was studied. Elevated p19 and p40 mRNA levels were found in PEC at 1 d.p.i., whereas p35 mRNA levels were not changed. Besides, the T(h)17-promoting cytokines IL-6, IL-1beta and transforming growth factor-beta were produced in response to S. Enteritidis. However, IL-6 was not required for IL-22 or IL-17A production by PEC. By ex vivo analysis of PEC at 1 d.p.i., we show that the major producers of early IL-12/23p40 in the peritoneal cavity were dendritic cells (DC), whereas macrophages notably contributed to IL-6 production. Taken together, these data suggest that DC initiate early IL-22 production at the site of infection which may contribute to resistance against salmonellosis. Furthermore, we provide evidence that production of IL-22 and IL-17A is differentially regulated during infection.

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