Regulatory T cells with superior immunosuppressive capacity emigrate from the inflamed colon to draining lymph nodes

Abstract

Foxp3 Regulatory T cells (Tregs) play a critical role in the maintenance of colon homeostasis. Here we utilized photoconvertible KikGR mice to track immune cells from the caecum and ascending (proximal) colon in the steady state and DSS-induced colitis. We found that Tregs from the proximal colon (colonic migratory Tregs) migrated exclusively to the distal part of mesenteric lymph nodes (dMLN) in an S1PR1-dependent process. In the steady state, colonic migratory CD25 Tregs expressed higher levels of CD103, ICOS, LAG3 and CTLA-4 in comparison with pre-existing LN Tregs. Intestinal inflammation led to accelerated Treg replacement in the colon, bidirectional Treg migration from the colon to dMLN and vice versa, as well as increases in Treg number, proliferation and expression of immunosuppressive molecules. This was especially apparent for CD25 very high Tregs induced in colitis. Furthermore, colonic migratory Tregs from the inflamed colon included more interleukin (IL)-10 producing cells, and demonstrated greater inhibition of T-cell proliferation in comparison with pre-existing LN Tregs. Thus, our results suggest that Tregs with superior immunosuppressive capacity are increased both in the colon and dMLN upon inflammation. These Tregs recirculate between the colon and dMLN, and are likely to contribute to the downregulation of intestinal inflammation.

ICOS+ Tregs: A Functional Subset of Tregs in Immune Diseases

“…Co-stimulation with ICOS was shown to downregulate CD62L and CCR7 while upregulating many chemokine ligands on CD4 + T cells, which led to reduced homing capacity to lymph nodes but increased accumulation of Treg cells in target tissues ( 60 , 61 ). For example, using photoconvertible fluorescent proteins to track Tregs recirculating between inflamed colon and the distal part of mesenteric lymph nodes, these migratory Tregs were discovered to display a highly immunosuppressive phenotype with a high expression of ICOS, Lag3, CTLA-4, CD103, PD-1, and CCR5 while exhibiting reduced expression of CCR7 ( 62 ). Intestinal inflammation increased Treg turnover as well as the number of Tregs with an inhibitory phenotype mentioned above, which contributed to controlling dextran sodium sulfate (DSS)-induced colitis ( 62 ).…”

“…For example, using photoconvertible fluorescent proteins to track Tregs recirculating between inflamed colon and the distal part of mesenteric lymph nodes, these migratory Tregs were discovered to display a highly immunosuppressive phenotype with a high expression of ICOS, Lag3, CTLA-4, CD103, PD-1, and CCR5 while exhibiting reduced expression of CCR7 ( 62 ). Intestinal inflammation increased Treg turnover as well as the number of Tregs with an inhibitory phenotype mentioned above, which contributed to controlling dextran sodium sulfate (DSS)-induced colitis ( 62 ). Additionally, except for ICOS + Tregs, Tr1 cells, Tfr cells, and B-cell induced CD4 + Foxp3 – regulatory T cells (Treg-of-B cells), which also highly express ICOS, can exert suppressive abilities in vitro and in vivo ( 6 , 63 ).…”

Immunological differences between colorectal cancer and normal mucosa uncover a prognostically relevant immune cell profile

“…This matches the idea of an inflammatory environment in the tumor, as Tregs with a superior immunosuppressive capacity have been recently reported in inflamed colon tissue. 49 Additionally, tumor T lymphocytes showed a reduced expression of CD69. This marker is expressed by resident memory T cells, promoting cell retention in the tissue.…”

Bryostatin‐1 ameliorated experimental colitis in Il‐10−/− Mice by protecting the intestinal barrier and limiting immune dysfunction

“…Over activated T helper cell type 1 (Th1) and T helper cell type 17 (Th17) immune responses contribute to intestinal damage in CD . Regulatory T cells (Tregs), which are required for controlling excessive inflammation and maintaining immune homeostasis, also play an essential role in the pathogenesis of CD . Undoubtedly, intestinal mucosal inflammation can indirectly or directly damage the intestinal barrier .…”

“…4 Regulatory T cells (Tregs), which are required for controlling excessive inflammation and maintaining immune homeostasis, also play an essential role in the pathogenesis of CD. 5 Undoubtedly, intestinal mucosal inflammation can indirectly or directly damage the intestinal barrier. 6 The intestinal epithelium at the interface between the intestinal microbiome/other antigens and the lymphoid tissue associated with the gastrointestinal system plays a critical role in shaping the mucosal immune response.…”