Critical role for the microbiota in limiting inflammatory intestinal T cell responses

Abstract

Abstract Efficient functioning of the intestine and intestinal immune system depends on interactions between the host and microbiota. Breakdown in these interactions leads to reduced ability to respond to intestinal pathogens along with increased intestinal inflammation which together can lead to pathologic inflammatory conditions such as inflammatory bowel disease. While a number of intestinal immune cells are likely regulated by the microbiota, we have found critical regulation of intestinal antigen presenting cells (APCs) expressing the chemokine receptor, CX3CR1. CX3CR1+ APCs are able to secrete both pro- and anti-inflammatory cytokines and are capable of mediating intestinal protection or pathology. Using in vivo models, we identified a regulatory loop whereby intestinal CX3CR1+ APCs reduced induction of Th1 cells against intestinal pathogens and promoted generation of regulatory T cells against soluble food antigens and the microbiota itself. This regulatory response depends on anti-inflammatory cytokine IL-10 production by CX3CR1+ APCs. Disruption of the intestinal microbiota switched the functional capacity of CX3CR1+ APCs so they now drove inflammatory Th1 responses and mediated pathology in a model of colitis. Mechanistically, we determined that epithelial attachment by intestinal microbes was required to turn on anti-inflammatory functions by CX3CR1+ APCs. Our results identify a cellular mechanism by which the microbiota limits intestinal inflammation and promotes homeostasis. Our study demonstrates the potential therapeutic benefits of microbiota and host immune cell manipulation with the goal of amplifying or inhibiting intestinal T cell responses.