Adaptive immunity and adipose tissue biology

Abstract

Studies of immunity typically focus on understanding how hematopoietic cells interact within conventional secondary lymphoid tissues. However, immune reactions and their regulation occur in various environments within the body. Adipose tissue is one tissue that can influence and be influenced by adjacent and embedded lymphocytes. Despite the abundance and wide distribution of such tissue, and despite a growing obesity epidemic, studies of these interactions have been only marginally appreciated in the past. Here, we review advances in understanding of lymphoid structures within adipose tissue, the relationship between adipose tissue and adaptive immune function, and evidence for how this relationship contributes to obesity-associated diseases.

Figure 1. B cells and adipose tissue

Fat-associated lymphoid clusters (FALC), omental milky spots (MS), and lean fat in general (blue boxes) have features favoring immune regulation. IL5 production by FALC sustains self-renewal of B1 B cells. B cells in this subset may produce IL10 and exert regulatory activity (Breg) [46,47]. B1 B cells also produce IgM, known to provide protection against influenza virus and also against bacteria such as Borrelia hermsii and S. pneumoniae. B1 cell-derived IgM against oxLDL may prevent this metabolite from exacerbating vascular atherosclerotic lesions. Omental and peritoneal B1 B cells also contribute to gut IgA production [45], important for oral tolerance and microbiota homeostasis. Incidentally, lean fat is enriched in TGFβ-producing regulatory T cells (Treg), which may provide this critical factor for IgA class switching. A Th2 bias in lean fat, including type 2 cytokine production by FALC cells, likely favors IgG1 production by conventional, B2 B lymphocytes. IgG1 against oral antigens contributes to oral tolerance in mice. Additionally, IgG1 against oxLDL may prevent or dampen vascular lesion formation by engaging the inhibitory Fc receptor (Fcγ RIIB) [83]. Th2 cytokine influence of B2 B cells may also promote IgE production favoring parasite expulsion. By contrast, obese fat (red boxes) tends to be in a pro-inflammatory state favoring exacerbation and/or initiation of autoimmune pathologies. This state includes a paucity of Tregs and a Th1 bias that may cooperate with B2 B cells to generate IgG2a/c. IgG2a/c against oral antigens in mice may contribute to poor oral tolerance (e.g., by complement fixation). IgG2a/c immune complexes with modified LDL may engage activating FcR (e.g., on macrophages) and exacerbate atherosclerotic lesions.

Figure 2. T cells and adipose tissue

Fat-associated lymphoid clusters (FALC), omental milky spots (MS), and lean fat in general (blue boxes) have features favoring immune regulation. A Th2 bias in lean fat may promote oral tolerance, parasite expulsion, and also prevent adipose expansion and inflammation. Lean fat is also enriched with regulatory T cells (Treg) that suppress multiple immune reactions, including expansion and activity of autoreactive lymphocytes, and also suppression of tumor immunity. Th17 cells are differentially regulated by obesity in distinct anatomical locations, and may contribute to autoimmune manifestations such as EAE. By contrast, obese fat (red boxes) has fewer Treg and a bias toward Th1 differentiation that likely contribute to the inflammatory state of obese adipose by stimulating macrophages and exacerbating autoimmune lesions. CD8 T cells may be differentially regulated by obese fat, depending on their involvement in autoimmunity versus infections.