Adipose Tissue Macrophages Are Innate to the Immunological Awareness of Adipose Tissue

The antigen-presentation process constitutes a fundamental basis of the functional immune system in vertebrates. The late Ralph Steinman, who discovered antigen-presenting dendritic cells, commented about the immune system that, “it is diverse beyond compare, tolerant without fail, and capable of behaving appropriately with a myriad of infections and other challenges” (1). Significant progress has been made in understanding the classical immune response to infections and rare failings of tolerance to self (2). However the underlying mechanisms of how the immune system processes and responds to “other challenges,” such as sensing and storage of caloric excess in adipose tissue and the integration of immune system with metabolism, remains largely unknown. Multiple studies during the past decade have identified visceral adipose tissue as an important site of residence of leukocytes, including cells of the innate (macrophages and neutrophils) and adaptive immune system (T and B cells) (3–5). It is clear that adipose tissue is a major endocrine organ that controls energy homeostasis. In addition, the presence of a significant number of hematopoietic cells in adipose tissue suggests that immune cells may impart unique immunological properties to the adipose tissue (4). For example, 1 g of enzymatically dispersed adipose tissues can contain up to 5 million stromal vascular fraction (SVF) cells, and after exclusion of adipocytes, w50–65% of SVF cells are leukocytes (6). Considering that in severe obesity in humans, the total fat content can constitute up to 50% of the total body mass, adipose tissue thus represents an uncharacterized immunological organ. For such an immunological characterization, specific cells in adipose tissue must be able to capture, process, and present antigens to T cells and mount a functional immunological response. In this issue, Morris et al. (7) further the hypothesis that adipose tissue is immunologically aware by providing tantalizing new evidence that adipose tissue macrophages (ATMs) serve as predominant antigen-presenting cells (APCs) that are fully competent to control the antigen-specific T-cell response in the adipose tissue of lean as well as obese mice. Many different nonhematopoietic cells expressing major histocompatibility complex (MHC) class I (MHC-I) can present antigen to CD8 T cells (cytotoxic cells). However, the professional APCs, such as the macrophages, dendritic cells, and B cells via the expression of MHC class II (MHC-II), present antigens to naïve CD4 T cells (helper cells) (1). Macrophages, through phagocytosis, can internalize extracellular antigens and process them in endosomes through proteolysis (8). MHC-II antigen presentation is the process whereby exogenous proteins are degraded, loaded onto an MHC-II molecule, and presented on the cell surface to CD4 T cells (8). A naïve T cell, via its T-cell receptor (TCR), is restricted to recognizing antigenic peptides only when bound to appropriate molecules of the MHC (9). Together with engagement of costimulatory molecules between macrophages–T cells, the naïve T cells differentiate into Th1, Th2, or Th17 effector cells that secrete specific cytokines to regulate immune responses (9). Morris et al. (7) demonstrate that high-fat diet (HFD) feeding enhances T-cell proliferation in the visceral fat pads but not in classical lymphoid organs, suggesting specific adipose-immune interactions. These data are consistent with several prior studies that show that obesity skews the T-cell repertoire in adipose tissue to mainly the effector type (6,10,11). Further examination in the current study revealed that exposure to an HFD caused effector T cells (mainly CD44) to undergo proliferation but not the naïve T cells (7). In noninfected young mice, CD44 effector-memory T cells in lymphoid organs are present in low frequency, usually below 20% (12). Interestingly, in obese mice fed the HFD, the proportion of CD44 effector cells in adipose tissue exceeds 60% and could be up to 90% (6,10,11). This would imply that in obesity, there may be an ongoing immune response in adipose tissue in the absence of overt infection or there is homeostatic proliferation of effector cells, a phenomenon associated with aging. Also, whether the adipose tissue effector CD44 cells are the descendants of naïve cells that are responding to adipose tissue–specific antigens or other gut-commensal microbe–derived antigens remains unknown. Morris et al. (7) provide evidence that HFD feeding increases MHC-II expression on ATMs and that most of this expression was localized in the “crown-like structures” and “fat-associated lymphoid clusters” in the adipose tissue, the major sites of macrophage residence in adipose tissue. Furthermore, HFD feeding increases the expression of costimulatory molecules on the ATMs (7). In the absence of the costimulation signal, the successful MHC-TCR interactions are not sufficient to induce a T-cell proliferation response and results in T-cell anergy (9). These data again suggest that HFD feeding imparts immunological properties to adipose tissue by supporting macrophage–T-cell interactions. As a proof of concept that ATMs can handle antigens, Morris et al. show that ATMs can process ovalbumin, a model antigen (7). Interestingly, a recent study by Deng et al. (13) challenged the existing paradigm of antigen presentation (1,8,9) From the Immunobiology Laboratory, Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, Louisiana. Corresponding author: Vishwa Deep Dixit, [email protected]. DOI: 10.2337/db13-0608 2013 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by -nc-nd/3.0/ for details. See accompanying original article, p. 2762.