MHCII expression on gut macrophages supports T cell homeostasis and is regulated by microbiota and ontogeny

Macrophages are traditionally considered antigen-presenting cells. However, their ability to present antigen and the factors regulating macrophage MHCII expression are poorly understood. Here, we demonstrate that MHCII expression on murine intestinal macrophages is differentially controlled by their residence in the small intestine (SI) or the colon, their ontogeny and the gut microbiota. Monocyte-derived macrophages are uniformly MHCIIhi, independently of the tissue of residence, microbial status or the age of the mouse, suggesting a common monocyte differentiation pathway. In contrast, MHCII expression on long-lived, prenatally-derived Tim4(+) macrophages is low after birth but significantly increases at weaning in both SI and colon. Furthermore, MHCII expression on colonic Tim4(+), but not monocyte-derived macrophages, is dependent on recognition of microbial stimuli, as MHCII expression is significantly downregulated in germ-free, antibiotic-treated and MyD88 deficient mice. To address the function of MHCII presentation by intestinal macrophages we established two models of macrophage-specific MHCII deficiency. We observed a significant reduction in the overall frequency and number of tissue-resident, but not newly arrived, SI CD4(+) T cells in the absence of macrophage-expressed MHCII. Our data suggest that macrophage MHCII provides signals regulating gut CD4(+) T cell maintenance with different requirements in the SI and colon.

Automated summary

This study demonstrates that the expression of MHCII on murine intestinal macrophages is regulated by their residence in the small intestine or the colon, ontogeny, and the gut microbiota. Monocyte-derived macrophages show consistent high expression of MHCII, while MHCII expression on long-lived, prenatally-derived macrophages increases significantly at weaning. Colonic macrophages' MHCII expression depends on recognition of microbial stimuli. Furthermore, macrophage-expressed MHCII plays a role in regulating the maintenance of gut CD4+ T cells with different requirements in the small intestine and the colon.