Mucosal tissue regulatory T cells are integral in balancing immunity and tolerance at portals of antigen entry

Abstract

Foxp3+ regulatory T cells (Tregs) are a subset of CD4+ T cells that exert suppressive control over other immune cells. Tregs are critical for preventing systemic autoimmunity and maintaining peripheral tolerance, and yet they also assist in orchestration of immunity to pathogenic insult, wherein they limit collateral immunopathology and assist in facilitating a fine balance between immune tolerance and effector activity. Tregs have been extensively studied in lymphoid tissues, and a growing body of work has characterized phenotypically distinct Tregs localized in various nonlymphoid tissue compartments. These tissue Tregs can perform location-specific, alternative functions, highlighting their dynamic, context-dependent roles. Tregs have also been identified in mucosal tissues where specialized physiological functions are paramount, including helping the host to respond appropriately to pathogenic versus innocuous antigens that are abundant at mucosal portals of antigen entry. As in other tissue Treg compartments, mucosal Tregs in the respiratory, gastrointestinal, and genitourinary tracts are distinct from circulating counterparts and can carry out mucosa-specific functions as well as classic suppressive functions that are the hallmark of Tregs. In this review, we summarize current knowledge regarding mucosal Tregs in both health and disease.

Fig. 1. Tregs in mucosal tissue sites help to balance active immunity versus immunological tolerance in the face of diverse antigenic exposures.

Mucosal barrier tissues serve as portals of entry to a wide variety of antigens, both harmful and harmless to the host. Thus, the mucosal immune system has the complex job of balancing tolerance to innocuous antigens such as food, allergens, semen, and commensals while at the same time patrolling for pathogens so that an appropriate immune response can be generated to benefit but not harm the host. Tregs, depicted here at the fulcrum of this balance, participate in this process of maintaining a homeostatic state of active immunosurveillance and tolerance rather than persistent mucosal inflammation.

Fig. 2. Mucosal tissue Tregs have both shared and specialized phenotypes and functions dependent on the tissue location.

Foxp3+ Tregs found throughout the body have immunosuppressive roles and can limit inappropriate inflammatory responses to self- and foreign antigens through a variety of mechanisms, including but not restricted to CTLA-4, ectoenzymes CD39 and CD73, IL-2 deprivation, and secretion of soluble regulatory mediators such as IL-10 and TGFβ. In addition, as has been demonstrated in non-mucosal and nonlymphoid tissues such as the visceral adipose tissue, skin, and muscle, Tregs can execute additional specialized functions that are induced by and meet the needs of their unique tissue environment. Here we highlight one example from each of the major mucosal tissue sites. In the respiratory tract, infection or inflammation can induce Tregs to produce amphiregulin, which promotes lung tissue repair. In the gastrointestinal tract, ingestion of dietary antigens early in life induces peripherally generated Tregs that are neuropilin-1 (NRP1) and Helios double-negative, as well as negative for the transcription factor RORγt. These cells have been shown to be critical for tolerance to dietary antigens, and so are major players in the prevention of food allergy. In addition, microbiota induces RORγt+c-Maf+ pTregs that are crucial to maintain tolerance to both food and commensal bacteria. Finally, exposure to sperm and seminal fluid induces an increase in the number of Tregs present in uterine tissues, and Tregs have a demonstrated role in preventing pre-eclampsia and gestational hypertension. Future work to characterize the unique phenotypic and functional traits of mucosal tissue Tregs will surely reveal additional novel roles for these cells in these barrier tissue compartments.