Contribution of Mesenteric Lymph Nodes and GALT to the Intestinal Foxp3+ Regulatory T-Cell Compartment

Abstract

SUMMARYThis study showed that the absence of CCR7 or mesenteric lymph nodes/gut-associated lymphoid tissue did not appreciably impact total intestinal Foxp3+ regulatory T cell representation in the steady-state. However, mesenteric lymph nodes/GALT are required for normal peripherally induced Foxp3+ regulatory T cell differentiation in the small intestine, but not in the large intestine.BACKGROUND & AIMSFoxp3+ regulatory T cells (Tregs) in the intestine promote immune tolerance to enteric antigens. Previous studies have shown that C-C chemokine receptor 7 (CCR7)-dependent migration of intestinal dendritic cells to the mesenteric lymph nodes (mLN) is involved in peripheral Foxp3+ Treg accumulation in the intestine and the establishment of oral tolerance. However, the relative contribution of this CCR7+ dendritic cell–mLN–Treg axis to the total intestinal Foxp3+ Treg pool during the steady-state remains unclear. In this study, the contribution of CCR7, as well as the mLN and gut-associated lymphoid tissue (GALT), to the intestinal Foxp3+ Treg compartment in the small intestine (SI) and large intestine (LI) was assessed.METHODSIntestinal Foxp3+ Tregs were quantitated in Ccr7−/− mice and in mice devoid of secondary lymphoid organs—including mLN and GALT—owing to a deficiency in lymphotoxin (LT) signaling. Specific analyses of Foxp3+Helios+ thymically derived (t)Tregs and Foxp3+Helios− peripherally derived (p) Tregs in the SI and LI, as well as the role for them LN in supporting Foxp3+ pTreg development using the B6.Cg-Tg(TcraTcrb) 425Cbn/J/ovalbumin (OVA) feeding system, were performed.RESULTSFoxp3+ Tregs were enriched in the intestine relative to the mLN, independent of CCR7. In the absence of the mLN and GALT, normal frequency and numbers of Foxp3+ Tregs were observed in LTα-deficient (Lta−/−) mice. However, Foxp3+Helios− pTregs were decreased in the SI of Lta−/− mice, corresponding with defective Foxp3+ pTreg expansion to OVA. In the LI, however, the proportion of Foxp3+Helios− pTregs and Foxp3+ pTreg induction to OVA was comparable between Lta−/− and Lta+/+ mice, which coincided with preferential expression of Treg-inducing/immunoregulatory cytokines.CONCLUSIONSThe overall size of the intestinal Foxp3+Treg pool is not impacted significantly by CCR7, mLN, or GALT during the steady-state. However, mLN/GALT appear to contribute to the Foxp3+ pTreg compartment in the SI, particularly in response to soluble oral antigen. These findings highlight important differences in the regulation of intestinal Tregs between the SI and LI, and suggest that enteric antigens may use mLN/GALT to induce Foxp3+ pTreg in the SI, while directly promoting Foxp3+ pTregs in the LI.

A B-Cell Gene Signature Correlates With the Extent of Gluten-Induced Intestinal Injury in Celiac Disease

“…In addition, regulatory B-cell subsets may be distinct from one another with unique tolerogenic phenotypes. Given these complexities, the peripheral B cell identified in this study may fall within the functional definition of regulatory B 39 and T 40 cells to dampen intestinal inflammation.…”

Induction of Colonic Regulatory T Cells by Mesalamine by Activating the Aryl Hydrocarbon Receptor

“…Interactions between indigenous intestinal miroflora and the host play a critical role in the accumulation of colonic, but not small intestinal, LP Tregs 7 . The commensals stimulate the differentiation, migration, and proliferation of Tregs in the colon LP,34, 35, 36 which may be independent on the MLNs 37 . In addition, colonic Tregs arise by means of commensal bacterial antigen-driven peripheral Treg development, thereby providing tolerance to commensal microbiota 38 .…”

“…In addition, colonic Tregs arise by means of commensal bacterial antigen-driven peripheral Treg development, thereby providing tolerance to commensal microbiota 38 . Thus, it is conceivable that colon LP is a unique site where Tregs are being constantly developed under the strong influence of commensal bacteria at steady state 36, 37. This unique Treg-developing microenvironment in the colon, but not in the small intestine, might somehow facilitate the promotion of colon LP Treg accumulation in response to mesalamine.…”

Developmental signifi cance of early gut-associated lymphoid tissue (GALT)- microbiota interactions in health and disease: Creating balance between tolerance and infl ammation in children

“…DCs also have the ability to extend their pseudopodia through the tight junctions to sample the antigens in the intestinal lumen [18,19]. APCs migrate to PPs or mesenteric lymph nodes and present processed antigen to naive T cells, which after acquiring the gut-homing ability, migrate to the lamina propria and epithelium [8,20,21]. Clones of the lymphocytes that reach the epithelium or lamina propria will be tolerant of the antigen previously presented by APCs.…”