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

Abstract

Obesity activates both innate and adaptive immune responses in adipose tissue, but the mechanisms critical for regulating these responses remain unknown. CD40/CD40L signaling provides bidirectional costimulatory signals between antigen-presenting cells and CD4 + T cells, and CD40L expression is increased in obese humans. Therefore, we examined the contribution of CD40 to the progression of obesity-induced inflammation in mice. CD40 was highly expressed on adipose tissue macrophages in mice, and CD40/CD40L signaling promoted the expression of antigen-presenting cell markers in adipose tissue macrophages. When fed a high fat diet, Cd40-deficient mice had reduced accumulation of con- ) in lean and obese fat was similar between wildtype and knockout mice. Adipose tissue macrophage content and inflammatory gene expression in fat did not differ between obese wild-type and knockout mice; however, major histocompatibility complex class II and CD86 expression on adipose tissue macrophages was reduced in visceral fat from knockout mice. Similar results were observed in chimeric mice with hematopoietic Cd40-deficiency. Nonetheless, neither whole body nor hematopoietic disruption of CD40 ameliorated obesityinduced insulin resistance in mice. In human adipose tissue, CD40 expression was positively correlated with CD80 and CD86 expression in obese patients with type 2 diabetes. These findings indicate that CD40 signaling in adipose tissue macrophages regulates major histocompatibility complex class II and CD86 expression to control the expansion of CD4 + T cells; however, this is largely dispensable for the development of obesity-induced inflammation and insulin resistance in mice.

Macrophage Proliferation Sustains Adipose Tissue Inflammation in Formerly Obese Mice

“…Cross-talk between macrophages and T cells is critical for the activation of both cell types in obesity (30,31). We evaluated costimulatory marker expression in eWAT ATMs from mice with WL.…”

“…Given the connection between antigen-presenting cells and T-cell activation in AT, we evaluated T-cell changes with WL (31,34,35). Weight cycling was shown to alter T-cell composition in AT (23), and we observed dynamic changes in AT T cells in our model as well.…”

Autoimmune responses and inflammation in type 2 diabetes

“…T cells are typically dependent on macrophages or dendritic cells (DCs) for their activation because of antigen presentation and costimulatory signals. Macrophages in adipose tissue can act as antigen‐presenting cells for CD4 + T cells, 54 and express CD40 which induces CD4 + T cells to induce major histocompatibility complex class II proteins (MHCII) and costimulatory molecule expression in the macrophages 55 . Recent evidence shows that adipocytes can express MHCII on their surface, enabling antigen presentation to CD4 + T cells in obesity‐induced insulin resistance 28 .…”

Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue

“…For example, deletion of chemokine (C-C motif) ligand 2 (CCL2) reduces ATM accumulation and improves insulin sensitivity in some but not all cases (5,6,15,16), while overexpression of CCL2 promotes insulin resistance (7). Moreover, chemical or genetic disruption of macrophages or their functions improves insulin sensitivity (17)(18)(19)(20)(21).…”