Both natural Treg and induced Treg play crucial roles in maintaining intestinal homeostasis. Paradoxically, significant numbers of Foxp3+Treg accumulate in the inflamed lesions in experimental colitis and IBD patients. Treg production of the effector cytokines IFNγ and/or IL-17 may explain their ineffectiveness in suppressing intestinal inflammation. However, it is unknown whether both iTreg and nTreg produce effector cytokines, and how TLR signaling regulates this process. We report here that Foxp3+Treg cells were increased in the intestines of TLR4-/- mice and colitic IL-10-/- mice. Deficiency in both TLR4 and IL-10 resulted in more severe colitis and further increased Treg cells in the inflamed intestines. The majority of Tregs in spleen are Fox3+ Helios+ Npn1+ nTreg whereas most Tregs in intestinal LP are Fox3+ Helios- Npn1- iTreg. Unexpectedly, more nTreg expressed IFNγ and/or IL-17 than iTreg in both spleen and intestine, which was further increased with TLR4 deficiency and intestinal inflammation. LPS-TLR4 signaling in both T cells and APC inhibited Foxp3+Treg via MyD88-dependent, TRIF-independent pathway, which was negatively regulated by SOCS3. These data demonstrate that intestinal inflammation drives iTreg expansion and induces effector cytokines by both nTreg and iTreg. TLR4 not only regulates intestinal inflammation, but also Treg conversion into Th1 and/or Th17. Further, both nTreg and iTreg phenotypes exhibit plasticity in the inflamed intestinal environment.
- Copyright © 2013 by The American Association of Immunologists, Inc.