Novel antigen-presenting cell imparts Treg-dependent tolerance to gut microbiota

Abstract

Establishing and maintaining tolerance to self-antigens or innocuous foreign antigens is vital for the preservation of organismal health. Within the thymus, medullary thymic epithelial cells (mTECs) expressing autoimmune regulator (AIRE) have a critical role in self-tolerance through deletion of autoreactive T cells and promotion of thymic regulatory T (Treg) cell development1–4. Within weeks of birth, a separate wave of Treg cell differentiation occurs in the periphery upon exposure to antigens derived from the diet and commensal microbiota5–8, yet the cell types responsible for the generation of peripheral Treg (pTreg) cells have not been identified. Here we describe the identification of a class of RORγt+ antigen-presenting cells called Thetis cells, with transcriptional features of both mTECs and dendritic cells, comprising four major sub-groups (TC I–TC IV). We uncover a developmental wave of Thetis cells within intestinal lymph nodes during a critical window in early life, coinciding with the wave of pTreg cell differentiation. Whereas TC I and TC III expressed the signature mTEC nuclear factor AIRE, TC IV lacked AIRE expression and was enriched for molecules required for pTreg generation, including the TGF-β-activating integrin αvβ8. Loss of either major histocompatibility complex class II (MHCII) or ITGB8 by Thetis cells led to a profound impairment in intestinal pTreg differentiation, with ensuing colitis. By contrast, MHCII expression by RORγt+ group 3 innate lymphoid cells (ILC3) and classical dendritic cells was neither sufficient nor required for pTreg generation, further implicating TC IV as the tolerogenic RORγt+ antigen-presenting cell with an essential function in early life. Our studies reveal parallel pathways for the establishment of tolerance to self and foreign antigens in the thymus and periphery, respectively, marked by the involvement of shared cellular and transcriptional programmes.

Intestinal epithelial HDAC3 and MHC class II coordinate microbiota-specific immunity

“…HDAC3-dependent MHCII expression specifically by epithelial cells limited accumulation of commensal-specific Th17 and thus, may be a dominant mechanism at the luminal surface for controlling commensal-specific CD4 + T cells and dampening pathogenic responses to the microbiota. In addition to controlling commensalspecific T cell accumulation, loss of epithelial HDAC3 or MHCII resulted in a significant reduction of commensal-specific Tregs, similar to recent observations with RORγt + antigen presenting cells (77)(78)(79). However, it is likely that CD4 + T cell responses to the microbiota reflect multiple signaling pathways in vivo that are not limited to HDAC3.…”

Novel “Thetis” antigen‐presenting cells promote early life gut immune tolerance

“…identified a subset of RORγt‐expressing cells thought to be a classical DC type 2 subset that expressed high levels of MHCII, CD86 and programmed death ligand 1 upon LPS exposure in vivo . The work by Akagbosu and Tayyebi et al 3 . thus clarifies the identity of RORγt‐expressing cells as a unique subset of RORγt + MHCII + APCs coined Thetis cells (TCs), critical for immune tolerance to the gut microbiota and prevention of intestinal inflammation during early life.…”

“…Akagbosu and Tayyebi et al 3 . have identified that the development of TCs coincides with pTreg expansion, suggesting the involvement of TCs in pTreg differentiation.…”

“…Although the developmental mechanisms promoting thymus‐derived Treg development in the thymus, including the involvement of the thymic antigen‐presenting cell (APC) autoimmune regulator ( Aire ) and medullary thymic epithelial cells (mTECs), are well established, 2 the regulatory mechanisms governing pTreg development and tolerance to gut microbiota remain unclear. A recent study by Akagbosu and Tayyebi et al 3 . has identified a new class of APC involved in pTreg development and establishing gut immune tolerance during early life.…”

Localization and movement of Tregs in gastrointestinal tract: a systematic review

“…ILC3 are activated by IL-1β + macrophage [30]. MHC class 2-positive ILC3 directly induce Rorγt + Tregs in colon, while CSF2 production from ILC3 indirectly induces Rorγt + Tregs through the activation of CD103 + DCs [74][75][76][77].…”