Salmonella has been a model pathogen for examining CD4 T cell activation and effector functions for many years due to the strength of the Th1 cell response observed during Salmonella infections, the relative ease of use of Salmonella, the availability of Salmonella-specific T cell reagents, and the well-characterized nature of the model system, the pathogen, and the immune response elicited. Herein, we discuss the use of Salmonella as a model pathogen to explore the complex interaction of T cells with their inflammatory environment. In particular, we address the issue of bystander activation of naïve T cells and non-cognate stimulation of activated and memory T cells. Further, we compare and contrast our current knowledge of these non-cognate responses in CD8 versus CD4 T cells. Finally, we make a case for Salmonella as a particularly appropriate model pathogen in the study of non-cognate CD4 T cell responses based on the strength of the Th1 response during infection, the requirement for CD4 T cells in bacterial clearance, and the well-characterized inflammatory response to conserved molecular patterns induced by Salmonella infection.

Th1 cells can be activated by TCR-independent stimuli, but the importance of this pathway in vivo and the precise mechanisms involved require further investigation. Here, we used a simple model of non-cognate Th1 cell stimulation in Salmonella-infected mice to examine these issues. CD4 Th1 cell expression of both IL-18R and DR3 was required for optimal IFN-γ induction in response to non-cognate stimulation, while IL-15R expression was dispensable. Interestingly, effector Th1 cells generated by immunization rather than live infection had lower non-cognate activity despite comparable IL-18R and DR3 expression. Mice lacking T cell intrinsic expression of MyD88, an important adapter molecule in non-cognate T cell stimulation, exhibited higher bacterial burdens upon infection with Salmonella, Chlamydia or Brucella, suggesting that non-cognate Th1 stimulation is a critical element of efficient bacterial clearance. Thus, IL-18R and DR3 are critical players in non-cognate stimulation of Th1 cells and this response plays an important role in protection against intracellular bacteria.

T cell effector functions can be elicited by noncognate stimuli, but the mechanism and contribution of this pathway to the resolution of intracellular macrophage infections have not been defined. Here, we show that CD4(+) T helper 1 (Th1) cells could be rapidly stimulated by microbe-associated molecular patterns during active infection with Salmonella or Chlamydia. Further, maximal stimulation of Th1 cells by lipopolysaccharide (LPS) did not require T-cell-intrinsic expression of toll-like receptor 4 (TLR4), interleukin-1 receptor (IL-1R), or interferon-γ receptor (IFN-γR) but instead required IL-18R, IL-33R, and adaptor protein MyD88. Innate stimulation of Th1 cells also required host expression of TLR4 and inflammasome components that together increased serum concentrations of IL-18. Finally, the elimination of noncognate Th1 cell stimulation hindered the resolution of primary Salmonella infection. Thus, the in vivo bactericidal capacity of Th1 cells is regulated by the response to noncognate stimuli elicited by multiple innate immune receptors.