CD4+ T cell immunity to Salmonella is transient in the circulation

While Salmonella enterica is seen as an archetypal facultative intracellular bacterial pathogen where protection is mediated by CD4+ T cells, identifying circulating protective cells has proved very difficult, inhibiting steps to identify key antigen specificities. Exploiting a mouse model of vaccination, we show that the spleens of C57BL/6 mice vaccinated with live-attenuated Salmonella serovar Typhimurium (S. Typhimurium) strains carried a pool of IFN-γ+ CD4+ T cells that could adoptively transfer protection, but only transiently. Circulating Salmonella-reactive CD4+ T cells expressed the liver-homing chemokine receptor CXCR6, accumulated over time in the liver and assumed phenotypic characteristics associated with tissue-associated T cells. Liver memory CD4+ T cells showed TCR selection bias and their accumulation in the liver could be inhibited by blocking CXCL16. These data showed that the circulation of CD4+ T cells mediating immunity to Salmonella is limited to a brief window after which Salmonella-specific CD4+ T cells migrate to peripheral tissues. Our observations highlight the importance of triggering tissue-specific immunity against systemic infections. Author summary Helper T cells are essential for controlling infections by bacterial pathogens, such as Salmonella enterica var Typhimurium (S. Typhimurium). While it is well-established that this role is related to their provision of IFN-γ, when and where helper T cells elicit their protective function in vivo remains unresolved. We identified a protective helper T cell population in the circulation of mice early after inoculation with growth-attenuated S. Typhimurium strains; this population waned overtime. We observed that circulating helper T cell immunity can adoptively protect naïve recipient mice against lethal S. Typhimurium infection when harvested from a short time-window. In comparing helper T cell responses between spleen and liver in Salmonella-infected mice, we have observed a previously uncharacterized trafficking of helper T cells to the liver followed by the residence of S. Typhimurium-specific T cell memory in the organ. Taken together these findings identify that protective immunity to Salmonella infections is transient in the circulation and the liver as a preferential site of helper T memory cells