Id2 is necessary for differentiation and survival of adipose-resident Tregs

Abstract Adipose regulatory T cells (aTregs) have emerged as critical cells for the control of local and systemic inflammation that is linked to health problems including type II diabetes and cardiovascular disease. While a number of factors are known to be required for aTreg survival, in this study we show a distinctive role for the transcriptional regulator Id2 in the maintenance and differentiation of aTregs. Here we show Id2 is highly expressed in aTregs compared to high Id3 expression in lymphoid Tregs. Treg-specific loss of Id2 resulted in a substantial decrease in the frequency of aTregs and a decrease in aTreg surface and intracellular markers while Tregs in the spleen and lymph nodes were unaffected. Gene expression analysis revealed that Id2 expression was essential for the survival of aTregs and loss of Id2 increased cell death in aTregs due to increased Fas expression. Surprisingly, we observed higher Hif1α expression in WT aTregs that diminished with loss of Id2. Thus, we reveal an unexpected role for Id2 in regulating survival of adipose-resident Tregs, critical cells for control of obesity-associated local and systemic inflammation.