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.

Deficiency of T cell CD40L has minor beneficial effects on obesity-induced metabolic dysfunction

“…Although we cannot rule out residual T cell CD40L activity, the fact that T effector cell numbers have decreased substantially suggests that the remaining CD40L + T cell population plays a minor role. Our results show that T cell CD40L is pivotal for the generation of CD4 + effector T cells and CD4 + Tregs, cell types that are considered major regulators of obesity-induced adipose tissue inflammation and insulin resistance 31 32. Adipose tissue T cell quantity and T cell subtype content correlates with BMI and waist circumference in patients with obesity and T2D.…”

“…Adipose tissue T cell quantity and T cell subtype content correlates with BMI and waist circumference in patients with obesity and T2D. During obesity, the number of Th2 cells and anti-inflammatory Tregs decreases in adipose tissue and are replaced with a gross increase in pro-inflammatory Th1 cells 31 32. Correlation between increased Th1 cells and altered glucose metabolism in DIO was found especially for patients with T2D, whereas in patients with obesity this correlation is less evident 33 34.…”

“…To maintain adipose tissue homeostasis Tregs are essential 31 32. These adipose tissue Tregs are predominantly induced Tregs (iTregs), which develop from naïve T cells, whereas natural Tregs (nTregs) develop in the thymus and largely depend on IL2 production 41 42.…”

Waist circumference is associated with major adverse cardiovascular events in male but not female patients with type-2 diabetes mellitus

“…Compared with BMI, waist circumference (WC) is a more effective surrogate measure of body fat distribution than BMI and strongly correlates with visceral adipose tissue [11,12]. Visceral adipose contributes significantly to inflammatory and metabolic complications of obesity [13][14][15][16]. However, visceral adipose continuously changes with age, and these changes are different between male and female patients [17].…”

Modeling Adipogenesis: Current and Future Perspective

“…Higher rates of vaccine failure have also been reported in individuals with obesity [ 23 ], perhaps due to compromised adaptive immunity. In all, the association of obesity with a compromised immune system, and a state of chronic low-grade inflammation in adipose tissue [ 24 ] is an indication of some degree of cross talk between adipocytes and cells of the immune system. Along with other cell types, such as endothelial and fibroblasts cells, lean adipose tissue contains macrophages for immunologic surveillance purposes.…”