Regulation, Communication, and Functional Roles of Adipose Tissue-Resident CD4+ T Cells in the Control of Metabolic Homeostasis

Abstract

Evidence accumulated over the past few years has documented a critical role for adipose tissue (AT)-resident immune cells in the regulation of local and systemic metabolic homeostasis. In the lean state, visceral adipose tissue (VAT) is predominated by anti-inflammatory T-helper 2 (Th2) and regulatory T (Treg) cell subsets. As obesity progresses, the population of Th2 and Treg cells decreases while that of the T-helper 1 (Th1) and T-helper 17 (Th17) cells increases, leading to augmented inflammation and insulin resistance. Notably, recent studies also suggest a potential role of CD4⁺ T cells in the control of thermogenesis and energy homeostasis. In this review, we have summarized recent advances in understanding the characteristics and functional roles of AT CD4⁺ T cell subsets during obesity and energy expenditure. We have also discussed new findings on the crosstalk between CD4⁺ T cells and local antigen-presenting cells (APCs) including adipocytes, macrophages, and dendritic cells (DCs) to regulate AT function and metabolic homeostasis. Finally, we have highlighted the therapeutic potential of targeting CD4⁺ T cells as an effective strategy for the treatment of obesity and its associated metabolic diseases.

Keywords: CD4+T cells; antigen-presenting cells; energy homeostasis; inflammation; insulin resistance; obesity.

Figure 1

Approaches to promote AT Treg cell accumulation in vivo. Injection of IL-33, the anti-CD3 antibody, or a complex consisting of recombinant IL-2 and a particular anti-IL-2 monoclonal antibody all show a long-lasting effect on Treg cell expansion in both lymphoid tissues and VAT. β-glucosylceramide induces iNKT cells activation which promotes Treg cells expansion via IL-2 production. In addition, adoptive transfer of Treg cells into recipient mice is recognized as a straight way to increase Treg populations. PPAR-γ agonist Pio treatment also specifically promotes VAT Treg cell accumulation.

Figure 2

Th2 and Treg cell-mediated immune responses in VAT under the lean state. In the lean state, activation and proliferation of AT-resident Th2 and Treg cells are mediated by APCs including M2 macrophages, CD11c ^highF4/80⁻ ATDCs, and maybe adipocytes with low MHCII expression. Activated Th2 cells produce type 2 cytokines including IL-4, IL-5, and IL-13, which together with iNKT and Treg cell-produced IL-10 further stimulate M2 activation. IL-10 also acts directly on adipocytes to promote insulin sensitivity. The homeostasis of Th2 and Treg cells is promoted by constitutively produced IL-33 from Cdh11⁺ mesenchymal cells, Pdpn⁺ fibroblasts, and CD31⁺ endothelial cells via high expression of ST2 on the surface of both cells. In addition, IL-33 and IFN-γ counter-regulate ILC2 activation to control Treg cell numbers. Besides, iNKT cells are necessary to sustain Treg cells via the production of IL-2. Together, these pathways contribute to metabolically healthy VAT.

Figure 3

Th1 and Th17 cell-mediated immune responses in VAT under the obese state. Overnutrition causes adipocyte hypertrophy, leading to the release of chemokines such as RANTES, which recruit proinflammatory CD4⁺ T cell accumulation in VAT via its receptor CCR5. Leptin secreted by adipocytes stimulates IFN-γ production from CD4⁺ T cells, which further promotes adipocyte MHCII expression and antigen-presentation to induce Th1 cell differentiation, leading to a vicious cycle of AT inflammation. Dead and neighboring adipocytes recruit M1 macrophages to WAT by producing inflammatory mediators such as MCP1 and CXCL12. Likewise, the expression of MHCII in M1 macrophages is promoted by IFN-γ, thus facilitating M1 macrophage-mediated antigen-presentation to induce Th1 cell differentiation. In addition, diet-induced obesity also promotes the expression of inflammatory receptor CD40 expression on ATMs and adipocytes as well as CD40L on CD4⁺ T cells, which reinforce the crosstalk between CD4 ⁺ T cells and these APCs. CD11c ^highF4/80 ^low ATDCs are also regarded as APCs to induce Th17 reactivation via production of TGF-β, IL-6, and IL-23. Type 1 cytokines such as TNF-α and IFN-γ, act directly on adipocytes to impair insulin action. Together with IL-6 and IL-1β, these cytokines elicit sustained chronic inflammation that eventually leads to insulin resistance.