Colitis interruptus: LAGing gut inflammation

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Science Immunology  07 Sep 2018:
Vol. 3, Issue 27, eaav0447
DOI: 10.1126/sciimmunol.aav0447


Regulatory T cells indirectly suppress ILC3-driven colitis by suppressing gut-resident macrophages in a LAG-3–dependent manner.

Regulatory T cells (Tregs) play a major role in suppressing inflammation in the gut. However, the mechanisms of this suppression remain unclear. In this paper, Bauché et.al. show that Tregs suppress group 3 innate lymphoid cells (ILC3)–driven colitis by suppressing interleukin-22 (IL-23) and IL-1β production by gut-resident macrophages. Furthermore, they show that latent activation gene-3 (LAG-3) on Tregs binds to major histocompatibility complex (MHC) class II on gut-resident macrophages to mediate this suppression.

The authors used an anti-CD40–induced colitis mouse model in which IL-22–producing ILC3 cells are known to play a key role in driving the disease pathology. Upon adoptive transfer of Tregs, they observed a reduction in IL-22-producing ILC3 cells and disease severity. Conversely, depletion of Tregs using Foxp3DTR mice led to an increase in IL-22–producing ILC3 cells and exacerbated disease severity. These results support a role for Tregs in suppressing ILC3-driven colitis. In vitro coculture experiments suggest that Tregs do not directly suppress ILC3 cells. Instead, they show that Tregs suppress IL-23 and IL-1β expression by CX3CR1+ gut-resident macrophages, which in turn leads to reduced IL-22–producing ILC3 cells. This effect of Tregs on macrophages is mediated through inhibition of CD40 and nuclear factor κB signaling in these cells. Tregs did not appear to have these suppressive effects on CD103+ dendritic cells, another cell type that produces IL-23 and IL-1β in the gut. Finally, they provide evidence that Treg suppression in this context is mediated by LAG-3 on these cells binding to MHC class II on macrophages, which acts to inhibit IL-23 and IL-1β from these cells. Taken together, this study uncovers a provocative mechanism of how LAG-3 expression on Tregs suppresses gut inflammation by regulating the activation of gut-resident macrophages. If validated in humans, augmentation of LAG-3 expressing Tregs may be a novel therapeutic strategy for the treatment of gut inflammation.

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