Regulatory T cells in peripheral tissue tolerance and diseases

Abstract

Maintenance of peripheral tolerance by CD4+Foxp3+ regulatory T cells (Tregs) is essential for regulating autoreactive T cells. The loss of function of Foxp3 leads to autoimmune disease in both animals and humans. An example is the rare, X-linked recessive disorder known as IPEX (Immune Dysregulation, Polyendocrinopathy, Enteropathy X-linked) syndrome. In more common human autoimmune diseases, defects in Treg function are accompanied with aberrant effector cytokines such as IFNγ. It has recently become appreciated that Tregs plays an important role in not only maintaining immune homeostasis but also in establishing the tissue microenvironment and homeostasis of non-lymphoid tissues. Tissue resident Tregs show profiles that are unique to their local environments which are composed of both immune and non-immune cells. Core tissue-residence gene signatures are shared across different tissue Tregs and are crucial to homeostatic regulation and maintaining the tissue Treg pool in a steady state. Through interaction with immunocytes and non-immunocytes, tissue Tregs exert a suppressive function via conventional ways involving contact dependent and independent processes. In addition, tissue resident Tregs communicate with other tissue resident cells which allows Tregs to adopt to their local microenvironment. These bidirectional interactions are dependent on the specific tissue environment. Here, we summarize the recent advancements of tissue Treg studies in both human and mice, and discuss the molecular mechanisms that maintain tissue homeostasis and prevent pathogenesis.

T cell and bacterial microbiota interaction at intestinal and skin epithelial interfaces

“…Tregs can derive from thymus precursors (tTregs) or be generated in the periphery (pTregs). Tolerance to gut microbes starts to be established during early life, but intestinal commensals are also critical to drive pTreg formation in the adult [ 1 , 90 , 91 ]. Tolerance to skin commensal bacteria is preferentially established in neonatal life with unique waves of activated regulatory T cells entering the skin [ 85 ].…”

“…Hence, most skin Treg cells belong to the tTreg-cell subset, while the intestine is richer in pTregs. Intestinal pTregs can be generated and function in the LP, the mLN, and TLS [ 90 , 92 ]. Paradoxically, the microbiota is dispensable for the early stages of peripheral regulatory T-cell induction within murine mesenteric LN [ 93 ].…”

“…Strikingly, IL-23 can inhibit IL-33 responsiveness in T cells, counteracting its Treg-promoting role [ 89 ]. The lamina propria is also augmented for Treg cells with high expression of RORγt, with most of such cells displaying constitutive expression of cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and inducible expression of IL-10, IL-35, and TGF-β [ 88 , 90 , 91 , 96 ]. Several bacterial species can induce the generation of FoxP3 +RORγt+ T cells in gnotobiotic mice, and in murine models of intestinal autoimmunity driven by T-cell transfer, the absence of Th17-like Treg cells can exacerbate pathogenesis, indicating its protective function [ 96 , 97 ].…”

Biomaterial-enhanced treg cell immunotherapy: A promising approach for transplant medicine and autoimmune disease treatment

“…Both tTregs and pTregs are found in various peripheral organs, yet the most prevalent generation of Tregs occurs within the gut [ 30 ]. Gut Tregs encompass both tTreg and pTreg populations.…”

“…Once they leave the thymus, tTregs become active in secondary lymphoid organs and further differentiate into effector Tregs within the gut. This transformation is triggered by signals such as IL-2, IL-33, TGF-β, and signals from microbiota, and their metabolites [ 30 ]. Recently, an alternative pathway for tTreg development has emerged in research.…”