Antigen- and Cytokine-Driven Accumulation of Regulatory T Cells in Visceral Adipose Tissue of Lean Mice

Abstract

SUMMARY A unique population of Foxp3+CD4+ regulatory T (Treg) cells, with a distinct transcriptome and antigen-receptor repertoire, resides in visceral adipose tissue (VAT) of lean individuals. These cells regulate local inflammation and both local and systemic metabolic indices. Here we focus on expansion of the VAT Treg compartment in aging lean mice – assessing these cells’ phenotypic conversion from conventional CD4+ T cells, influx from lymphoid organs, and local population dynamics. Our findings establish that the VAT Treg compartment is seeded from thymocytes generated during the first weeks of life, and expands beyond 10 weeks of age due to indolent proliferation, of certain clones in particular, coupled with enhanced survival. Accumulation of VAT Tregs depends on antigen(s) presented by MHC class-II molecules and soluble mediators, notably interleukin(IL)-33. Addressing such factors therapeutically promises novel approaches for harnessing Tregs to stem the growing epidemic of obesity and consequent metabolic abnormalities.

Peri-alloHCT IL-33 administration expands recipient T-regulatory cells that protect mice against acute GVHD

“…[37][38][39][40][41] Although mechanisms controlling IL-33 pleiotropy are unclear, its activity is controlled by both the regulated availability of ST2-expressing cells, as well as the presence of proinflammatory cytokines. 57,58 Recipient conditioning prior to alloHCT causes a breach in the intestinal epithelium that allows commensal bacteria to trigger proinflammatory cytokine secretion by local macrophages and DCs.…”

“…32 Although IL-33 expands Tregs 38,39,41 and supports Treg stability, 37 when physiologic ratios of donor Tregs to non-Tregs were transferred into alloHCT recipients, endogenous or exogenous IL-33 stimulation of Tregs posttransplant was insufficient to prevent lethal GVHD. 32 The data depicted in Figures 1-3 BLOOD, 21 JULY 2016 x VOLUME 128, NUMBER 3…”

“…[33][34][35][36] In addition to its potent type 1-and type 2-promoting capacity, a growing body of research supports a role for IL-33 in Treg immunobiology. [37][38][39][40][41][42] Our group and others have described a subset of Foxp3 In nonlymphoid compartments, ST2 1 Tregs are present at increased frequencies and would be well positioned to respond to IL-33 released from damaged tissue. 37,42 Despite these interesting observations, there are no definitive studies examining the impact of both donor and host IL-33-responsive Tregs after alloHCT.…”

Unstable FoxP3 + T regulatory cells in NZW mice

“…Cytokines-IL-2 foremost-are thought to be the main controllers of Treg proportions and numbers (15)(16)(17)(18)(19)(20)(21)(22), although the relative importance of these controllers varies with location and subphenotype [e.g., the alarmin IL-33 has a more profound role in tissue Tregs (21)(22)(23)]. Perhaps surprisingly, in light of this apparently tight control, there is a wide range of variation in Treg proportions, with several studies having observed up to fourfold variation in the blood of healthy humans (e.g., refs.…”

CD40 promotes MHC class II expression on adipose tissue macrophages and regulates adipose tissue CD4+ T cells with obesity

“…Adipose tissue inflammation involves activation of both innate and adaptive immune responses [1,2]. MHC class II-restricted signals from macrophages and dendritic cells contribute to T cell activation in response to obesogenic cues and contribute to metabolic dysfunction [3][4][5]. ATMs and dendritic cells can function as APCs and provide critical cues to generate proinflammatory signals that include activation of adipose tissue CD4 + T cells toward a Th1 and effector/memory phenotype [6][7][8].…”