Redundant cytokine requirement for intestinal microbiota-induced Th17 cell differentiation in draining lymph nodes

Abstract

Differentiation of intestinal T helper 17 (Th17) cells, which contribute to mucosal barrier protection from invasive pathogens, is dependent on colonization with distinct commensal bacteria. Segmented filamentous bacteria (SFB) are sufficient to support Th17 cell differentiation in mouse, but the molecular and cellular requirements for this process remain incompletely characterized. Here we show that intestine-draining mesenteric lymph nodes (MLN) are the dominant site of SFB-induced intestinal Th17 cell differentiation. Subsequent migration of these cells to the intestinal lamina propria is dependent on their up-regulation of integrin b7. Stat3-dependent induction of RORgt, the Th17 cell-specifying transcription factor, largely depends on IL-6, but signaling through the receptors for IL-21 and IL-23 can compensate for absence of IL-6 to promote SFBdirected Th17 cell differentiation. These results indicate that redundant cytokine signals guide commensal microbe-dependent Th17 cell differentiation in the MLN and accumulation of the cells in the lamina propria.

Update on immunosuppressive strategies in intestinal transplantation

“…Just as these cells respond to TNFa-blockade by infliximab in severe refractory IBD, 14 of 14 ITx patients with thymoglobulin-refractory rejection showed improved clinical and histological score after treatment with infliximab. Besides making the case for clinical trials incorporating infliximab into the treatment algorithm for refractory intestinal rejection, this study also raises interesting questions about which aspects of the Th17 pathway are inflammatory rather than protective, since blocking IL-17 entirely causes increased inflammation in some cases, likely because IL-17 has functions that are essential for protection from intestinal pathogens and for maintaining homeostasis between the gut mucosa and commensals through various pathways involving IL-22, IL-10, serum amyloid A, STAT3, and IL-10 [25]. Thus, another important recent concept about novel immunomodulatory treatments after intestinal transplantation is that, unlike TNFa-blockade, which preferentially targets pathological Th17 responses, IL-17 blockade is not a promising direction and, more broadly, that it is important to consider the range of cytokine functions when blocking entire pathways.…”