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

Abstract

As CD4+CD25+Foxp3+ regulatory T cells (Tregs) play crucial immunomodulatory roles during infections, one key question is how these cells are controlled during antimicrobial immune responses. Mechanisms controlling their homeostasis are central to ensure efficient protection against pathogens, as well as to control infection-associated immunopathology. Here we studied how their viability is regulated in the context of mouse oropharyngeal candidiasis (OPC) infection, and found that these cells show increased protection from apoptosis during late phase of infection and reinfection. Tregs underwent reduced cell death because they are refractory to Tcell receptor restimulation-induced cell death (RICD). We confirmed their resistance to RICD, using mouse and human Tregs in vitro, and by inducing α-CD3 antibody-mediated apoptosis in vivo. The enhanced viability is dependent on increased transforming growth factor-β1 (TGF-β1) signaling that results in upregulation of cFLIP (cellular FLICE (FADD-like IL-1β-converting enzyme)-inhibitory protein) in Tregs. Protection from cell death is abrogated in the absence of TGF-β1 signaling in Tregs during OPC infection. Taken together, our data unravel the previously unrecognized role of TGF-β1 in promoting Treg viability, coinciding with the pronounced immunomodulatory role of these cells during later phase of OPC infection, and possibly other mucosal infections.

TGF-β and VEGF cooperatively control the immunotolerant tumor environment and the efficacy of cancer immunotherapies

“…TGF-β inactivation had a largely direct effect on Tregs, with decreased tumor infiltration and increased apoptosis, in line with its known properties (34,37,47). In contrast, the effect of VEGF on Treg appears more indirect.…”

IL-1β-MyD88-mTOR Axis Promotes Immune-Protective IL-17A+Foxp3+ Cells During Mucosal Infection and Is Dysregulated With Aging

“…To test this hypothesis, we treated the cells with heat killed Candida albicans germ tube (HKGT) (10 7 /ml), α-CD3 (1 μg/ml, α-CD28 (2 μg/ml), and TGF-β1 (5 ng/ml), to examine the frequency of Foxp3 + cells after 5 days. We employed this in vitro cell culture system because: 1) We have previously found that HKGT can cause in vitro proliferation of T regs in TLR-2 dependent manner; 2) TGF-β1 is important for survival of Foxp3 + T regs during oral CA infection as well resistance to Candida in vivo ( 2 , 32 , 33 ); and 3) Activating T cells in a whole tissue culture system including the local antigen presenting cells (APC) is more physiological than using purified T cell cultures because APC secrete appropriate cytokines in the milieu ( 2 , 32 ). As expected, HKGT stimulation increased the proportion of Foxp3 + cells among CD4 + T cells in FYcre cultures compared to those found ex vivo ( Figures 1A, C , upper panel).…”

Mucosal Regulatory T Cells and T Helper 17 Cells in HIV-Associated Immune Activation

“…We hypothesize that increased proportions of T regs may also be attributed to preferential apoptosis or pyroptosis of conventional CD4 + T cells, including Th17 cells in the mucosa. We have previously shown that conventional CD4 T effector cells are highly susceptible to FAS-mediated apoptosis compared to T regs in vitro and in vivo ( 145 ). In our future studies, we will examine whether differential sensitivities of Th17 cells and T reg cells to FAS mediated apoptosis and, or pyroptosis, also contribute to increased T reg /Th17 ratio in mucosa during HIV infection.…”