CD4+ T cell control of Salmonella infection and persistence is dependent on different macrophage subsets

Abstract

Abstract The control of the persistent phagosomal pathogen, Salmonella enterica (Se), by the adaptive immune system is dependent on pathogen-specific CD4+ T-helper 1 (Th1) cells. To explore the hypothesis that Se uses a specific cellular niche to evade Th1 cells in order to persist, we generated a strain of Se that expresses a chromosomally-encoded dTomato protein that displays bright and stable fluorescence in vivo. Following oral infection in 129sv/J mice we found dTomato+ cells in macrophage (MΦ), monocyte, and neutrophil populations. Depletion of neutrophils during infection had no effect on bacterial burden or survival. In contrast, depletion of monocytes and MΦ in CCR2 or LysM-Cre CD115 stop-flox diphtheria toxin (DT) receptor transgenic mice increased bacterial counts and death 6–8 days after DT treatment, indicating an important role for these cells in maintaining Se persistence. Depletion of CD4+ T cells led to increases in bacterial counts and an altered infected cell profile compared to control animals. The frequency of infected CD11bHi MerTKInt infiltrating MΦ was increased, while infected CD11bIntMerTKHi tissue resident MΦ remained relatively constant, suggesting that Th1 cells interact preferentially with infiltrating MΦ. Infected tissue resident MΦ expressed less MHCII, CD86 and more PD-L1 and PD-L2 than uninfected counterparts, and a reciprocal expression pattern was observed on infected infiltrating MΦ. These data suggest that Th1 cells promote killing of intracellular Se in infiltrating MΦ and either ignore or are inhibited by infected tissue resident MΦ providing a reservoir where Se can persist for the lifetime of the infected animal.