Adaptive Immunity and Antigen-Specific Activation in Obesity-Associated Insulin Resistance

Abstract

Type 2 diabetes mellitus (T2D) is a metabolic disease that is strongly tied to obesity and often preceded by insulin resistance (IR). It has been established that chronic inflammation of hypertrophic adipose tissue depots in obese individuals leads to obesity-associated IR and is mediated by cells of the innate immune system, particularly macrophages. More recently, cells of the adaptive immune system, B and T lymphocytes, have also emerged as important regulators of glucose homeostasis, raising the intriguing possibility that antigen-driven immune responses play a role in disease. In this review, we critically evaluate the roles that various B and T cell subsets play in IR, and then we examine the data suggesting that antigen-driven mechanisms, such as antigen presentation and costimulation, may drive the activity of these lymphocytes.

Figure 1

Possible antigen-specific processes in IR pathogenesis. The antigens targeted in IR can come either from self or external sources, so long as they are chronically available to the adaptive immune system. Necrotic death of adipocytes is one potential source of autoantigen (1). External sources of antigen include gut microbiota and dietary antigens, which may enter the circulation passively due to increased intestinal permeability or via chylomicron transport (2). When the antigen is present within the inflamed surroundings of the adipose tissue, B cells can recognize the antigen directly through their surface Ig receptors (3). Alternatively, soluble antibody can bind to the antigen and enable opsonization by macrophages or dendritic cells, which then process and present the antigen on MHC-II to cognate naïve T cells (4). Adipocytes can also present antigen on MHC-II directly to T cells (5). If the T cell recognizes a correct peptide-MHC pair and receives CD28 stimulation and cytokine signals, it differentiates into effector T cells (6). A few of these cells form memory T cells which have a lower threshold for activation when they encounter the same antigen again (7). Activated T cells can also become follicular helper T cells which enter the germinal center to provide help to activated B cells that recognize antigens from the same antigen source (8). Activated B cells present antigen to follicular helper T cells and receive stimulation through their CD40 coreceptors (8), which licenses the cells to undergo antibody class switching, somatic hypermutation, and formation of memory B cells or long-lived plasma cells. Memory B cells also have a lower threshold for activation in a repeat encounter with antigen while the plasma cells maintain somatically hypermutated antibody production for the antigen (9). From these interactions, a strong, specific, and chronic immune response develops that leads to obesity-related IR. Not shown in this diagram are the regulatory cells that help to modulate these processes, for example, Tregs, Th2 cells, B-1a, and Breg cells.