Mutual antagonism of TGF-beta and Interleukin-2 in cell survival and lineage commitment of induced regulatory T cells

Abstract

Transforming growth factor beta (TGF-b)-and Interleukin-2 (IL-2)-mediated signaling enables the generation and expansion of induced regulatory T (iTreg) cells that carry high hopes for the treatment of chronic inflammatory and autoimmune diseases. Knowledge about factors stabilizing their lineage commitment and lifespan, however, is limited. Here, we investigated the behavior of iTreg cells, derived from apoptosis-defective mouse mutants, during activated cell autonomous cell death, triggered by cytokine-deprivation, or activation-induced cell death (AICD) after restimulation of the T-cell receptor, and compared these responses with those of effector T cells. We observed that iTreg cells were much more sensitive to IL-2-deprivation but poorly susceptible to AICD. In fact, when apoptosis was compromised, T-cell receptor (TCR)-religation resulted in methylationindependent, ERK-and PI3K/mTOR-mediated loss of Foxp3 expression, impaired suppressive capacity and effector cytokine production. Although iTreg cells prevented colitis induction they rapidly lost Foxp3-GFP expression and gained ability to produce effector cytokines thereby imposing Th1 cell fate on resident effector cells. Surprisingly, iTreg cell conversion itself was limited by TGF-b-mediated Bim/Bcl2L11-dependent apoptosis. Hence, the very same cytokine that drives the generation of iTreg cells can trigger their demise. Our results provide novel insights in iTreg cell biology that will assist optimization of iTreg-based therapy.

Transforming growth factor-β1 sustains the survival of Foxp3+ regulatory cells during late phase of oropharyngeal candidiasis infection

“…Similar to T regs and consistent to a previous publication, in vitro T regs also showed decreased apoptosis (Figure 5d). 24 Although TGF-β did not inhibit proliferation in in vitro T regs , these cells also showed reduced active caspase levels compared with T cons upon RICD induction (Supplementary Figure S7A,B). Taken together, these results show that TGF-β plays a crucial role in reducing TCR-induced RICD.…”

“…19,20 It is well known that along with T regs , RICD 8,9,21 and cytokine withdrawal-induced death are also 10,16 required for immune homeostasis following antigen clearance during infections. 22,23 Although Bim and transforming growth factor-β1 (TGF-β1) have been implicated in regulating the size of T regs , 24,25 their role in T reg RICD is unknown. Two in vitro studies have examined RICD in T regs , but the mechanistic details and the physiological relevance were not explored.…”

Mathematical model of sarcoidosis

“…Treg cells are activated by TGF-β in the presence of IL-2 (18,19) and direct contact with activated macrophages and chemoattracted by CCL20 (14). TNF-α resists activation of Treg (28), and this resistance is assumed to be significantly higher than the internalization of TGF-β (which is neglected here).…”

“…Treg and Th17 are both activated by TGF-β (15). IL-2 secreted by Th1 (16) increases the proliferation of Th1 cells (16), blocks the proliferation of Th17 cells (17), and enhances the activation of Treg by TGF-β (18,19); TGF-β is secreted by activated macrophages and Treg (20,21).…”

Metabolic profiling of human CD4+ cells following treatment with methotrexate and anti-TNF-α infliximab

“…Inflammation is triggered in response to tissue injury or infection, and mounting an inflammatory response is an energy-intensive process. The products of inflamed tissues that provoke inflammation can activate T cells 16 - 18 . Indeed, T cells are prime examples of how cell metabolism can be dramatically altered to support the specific needs and functions of each cell state.…”