Drastic transformation of visceral adipose tissue and peripheral CD4 T cells in obesity

Abstract

Obesity has a pronounced effect on the immune response in systemic organs that results in not only insulin resistance but also altered immune responses to infectious diseases and malignant tumors. Obesity-associated microenvironmental changes alter transcriptional expression and metabolism in T cells, leading to alterations in T-cell differentiation, proliferation, function, and survival. Adipokines, cytokines, and lipids derived from obese visceral adipose tissue (VAT) may also contribute to the systemic T-cell phenotype, resulting in obesity-specific pathogenesis. VAT T cells, which have multiple roles in regulating homeostasis and energy utilization and defending against pathogens, are most susceptible to obesity. In particular, many studies have shown that CD4 T cells are deeply involved in the homeostasis of VAT endocrine and metabolic functions and in obesity-related chronic inflammation. In obesity, macrophages and adipocytes in VAT function as antigen-presenting cells and contribute to the obesity-specific CD4 T-cell response by inducing CD4 T-cell proliferation and differentiation into inflammatory effectors via interactions between major histocompatibility complex class II and T-cell receptors. When obesity persists, prolonged stimulation by leptin and circulating free fatty acids, repetitive antigen stimulation, activating stress responses, and hypoxia induce exhaustion of CD4 T cells in VAT. T-cell exhaustion is characterized by restricted effector function, persistent expression of inhibitory receptors, and a transcriptional state distinct from functional effector and memory T cells. Moreover, obesity causes thymic regression, which may result in homeostatic proliferation of obesity-specific T-cell subsets due to changes in T-cell metabolism and gene expression in VAT. In addition to causing T-cell exhaustion, obesity also accelerates cellular senescence of CD4 T cells. Senescent CD4 T cells secrete osteopontin, which causes further VAT inflammation. The obesity-associated transformation of CD4 T cells remains a negative legacy even after weight loss, causing treatment resistance of obesity-related conditions. This review discusses the marked transformation of CD4 T cells in VAT and systemic organs as a consequence of obesity-related microenvironmental changes.

The interplay between obesity, immunosenescence, and insulin resistance

“…As obesity progresses, antigens (likely self-peptides) on MHCII molecules are known to stimulate T-cell proliferation and differentiation into specific subclasses of inflammatory effectors. The persistence of VAT inflammation can be due to this factor [ 66 ]. Moreover, obese individuals have elevated levels of leptin, which can trigger the activation of T-cells and facilitate their transformation into the interferon‐gamma (IFN‐γ) -producing type 1 T helper (Th1) phenotype [ 42 ].…”

“…This can be a significant indicator of immunosenescence [ 64 ]. Accumulation of lipids leads to an increase in IL-6, leukemia inhibitory factor, and oncostatin M, which impede thymic functions and trigger thymocyte apoptosis [ 66 ]. When obesity decreases thymic output, peripheral T-cells undergo extensive homeostatic proliferation, which may result in T- cell senescence.…”

“…The cell surface molecule PD-1, mediates immune suppression. Individuals with obesity have a higher level of PD-1 expression on their T-cells [ 66 ]. The B cells and macrophages in VAT can also strongly express programmed death-ligand 1 [ 23 ].…”

“…CD153 + PD-1hi CD4 T-cells are senescence-associated T-cells that were initially identified as a distinct subset of T-cells. They emerge during aging or obesity and are a part of the process of chronic local inflammation [ 66 ]. B-cells are partly responsible for the generation of CD153 + PD-1hi CD4 T-cells in VAT, which in turn contribute to inflammation and metabolic disorders in obesity.…”

A Role of Sodium-Glucose Co-Transporter 2 in Cardiorenal Anemia Iron Deficiency Syndrome

“…The author found that in a mouse model of obesity induced by a high-fat diet, CD4 + T lymphocytes in secondary lymph nodes and visceral adipose tissue showed accelerated cellular senescence. These CD4 + T lymphocytes, which have acquired a strong inflammatory phenotype and are not suppressed by the immune checkpoint molecules programmed cell death 1 receptor and its ligand programmed cell death ligand 1, are the trigger of chronic inflammation and increased insulin resistance in visceral adipose tissue [ 69 , 70 , 71 ].…”