Caspase-8 has dual roles in regulatory T cell homeostasis balancing immunity to infection and collateral inflammatory damage.

Targeting the potent immunosuppressive properties of FOXP3+ regulatory T cells (Tregs) has substantial therapeutic potential for treating autoimmune and inflammatory diseases. Yet, the molecular mechanisms controlling Treg homeostasis, particularly during inflammation, remain unclear. We report that caspase-8 is a central regulator of Treg homeostasis in a context-specific manner that is decisive during immune responses. In mouse genetic models, targeting caspase-8 in Tregs led to accumulation of effector Tregs resistant to apoptotic cell death. Conversely, inflammation induced the MLKL-dependent necroptosis of caspase-8-deficient lymphoid and tissue Tregs, which enhanced immunity to a variety of chronic infections to promote clearance of viral or parasitic pathogens. However, improved immunity came at the risk of lethal inflammation in overwhelming infections. Caspase-8 inhibition using a clinical-stage compound revealed that human Tregs have heightened sensitivity to necroptosis compared with conventional T cells. These findings reveal a fundamental mechanism in Tregs that could be targeted to manipulate the balance between immune tolerance versus response for therapeutic benefit.

Attenuation of TCR-induced transcription by Bach2 controls regulatory T cell differentiation and homeostasis.

Differentiation and homeostasis of Foxp3+ regulatory T (Treg) cells are strictly controlled by T-cell receptor (TCR) signals; however, molecular mechanisms that govern these processes are incompletely understood. Here we show that Bach2 is an important regulator of Treg cell differentiation and homeostasis downstream of TCR signaling. Bach2 prevents premature differentiation of fully suppressive effector Treg (eTreg) cells, limits IL-10 production and is required for the development of peripherally induced Treg (pTreg) cells in the gastrointestinal tract. Bach2 attenuates TCR signaling-induced IRF4-dependent Treg cell differentiation. Deletion of IRF4 promotes inducible Treg cell differentiation and rescues pTreg cell differentiation in the absence of Bach2. In turn, loss of Bach2 normalizes eTreg cell differentiation of IRF4-deficient Treg cells. Mechanistically, Bach2 counteracts the DNA-binding activity of IRF4 and limits chromatin accessibility, thereby attenuating IRF4-dependent transcription. Thus, Bach2 balances TCR signaling induced transcriptional activity of IRF4 to maintain homeostasis of thymically-derived and peripherally-derived Treg cells.

c-Maf-dependent Treg cell control of intestinal TH17 cells and IgA establishes host-microbiota homeostasis.

Foxp3+ regulatory T cells (Treg cells) are crucial for the maintenance of immune homeostasis both in lymphoid tissues and in non-lymphoid tissues. Here we demonstrate that the ability of intestinal Treg cells to constrain microbiota-dependent interleukin (IL)-17-producing helper T cell (TH17 cell) and immunoglobulin A responses critically required expression of the transcription factor c-Maf. The terminal differentiation and function of several intestinal Treg cell populations, including RORγt+ Treg cells and follicular regulatory T cells, were c-Maf dependent. c-Maf controlled Treg cell-derived IL-10 production and prevented excessive signaling via the kinases PI(3)K (phosphatidylinositol-3-OH kinase) and Akt and the metabolic checkpoint kinase complex mTORC1 (mammalian target of rapamycin) and expression of inflammatory cytokines in intestinal Treg cells. c-Maf deficiency in Treg cells led to profound dysbiosis of the intestinal microbiota, which when transferred to germ-free mice was sufficient to induce exacerbated intestinal TH17 responses, even in a c-Maf-competent environment. Thus, c-Maf acts to preserve the identity and function of intestinal Treg cells, which is essential for the establishment of host-microbe symbiosis.

Development and Function of Effector Regulatory T Cells.

Distinguishing self from nonself is a unique feature of the immune system. Although most self-reactive T cells are eliminated in the thymus, a few rogue cells escape the negative selection process and have the potential to mediate autoimmune disease. Over the last decade, there has been a vast improvement in our understanding of the cellular mechanisms that evolved to dampen the deleterious effects of these self-reactive T cells. In particular, T cells expressing the transcription factor FoxP3, known as regulatory T (Treg) cells, play a central role in maintaining immune homeostasis and suppressing autoimmune responses. In addition, Treg cells are endowed with the ability to suppress diverse inflammatory responses both in lymphoid and in nonlymphoid tissues. This requires Treg cells to undergo a peripheral differentiation and specialization program that results in the emergence of effector Treg (eTreg) cells that are characterized by their ability to produce high amounts of immunosuppressive molecules, including IL-10. This chapter discusses the recent advances in our understanding of the mechanisms governing the differentiation, migration, and maintenance of eTreg cells, in particular in nonlymphoid tissues, in health and disease.