Summary Co-inhibitory receptors, such as CTLA-4 and PD-1, have an important role in regulating T cell responses and have proven to be effective targets in the setting of chronic diseases where constitutive co-inhibitory receptor expression on T cells dampens effector T cell responses. Unfortunately, many patients still fail to respond to therapies that target CTLA-4 and PD-1. The next wave of co-inhibitory receptor targets that are being explored in clinical trials include Lag-3, Tim-3, and TIGIT. These receptors while belonging to the same class of receptors as PD-1 and CTLA-4 exhibit unique functions especially at tissue sites where they regulate distinct aspects of immunity. Increased understanding of the specialized functions of these receptors will inform the rational application of therapies that target these receptors to the clinic.

Summary Foxp3+ T regulatory (Treg) cells regulate immune responses and maintain self-tolerance. Recent work shows that Treg cells are comprised of many subpopulations with specialized regulatory functions. Here we identified Foxp3+ T cells expressing the co-inhibitory molecule TIGIT as a distinct Treg cell subset that specifically suppresses pro-inflammatory T helper 1 (Th1) and Th17 cell, but not Th2 cell responses. Transcriptional profiling characterized TIGIT+ Treg cells as an activated Treg subset with high expression of Treg signature genes. Ligation of TIGIT on Treg cells induced expression of the effector molecule fibrinogen-like protein 2 (Fgl2), which promoted Treg cell-mediated suppression of T effector cell proliferation. In addition, Fgl2 was necessary to prevent suppression of Th2 cell cytokine production in a model of allergic airway inflammation. TIGIT expression therefore identifies a Treg cell subset that demonstrates selectivity for suppression of Th1 and Th17 cell but not Th2 cell responses.

IL-10 producing regulatory type 1 (TR1) T cells are instrumental in the prevention of tissue inflammation, autoimmunity and graft-versus-host disease. The transcription factor c-Maf is essential for TR1 induction of IL-10, but the molecular mechanisms leading to the development of these cells remain incompletely understood. We demonstrate that the ligand–activated transcription factor aryl hydrocarbon receptor (AhR) induced by IL-27, synergizes with c-Maf to promote the development of TR1 cells. Upon T cell activation under TR1-skewing conditions, the AhR binds to c-Maf and promotes the transactivation of both Il10 and Il21 promoters, resulting in the generation of TR1 cells and amelioration of experimental autoimmune encephalomyelitis. Manipulation of AhR signaling could therefore be beneficial in the resolution of excessive inflammatory responses.