I thank Drs. Gomez-Mejiba and Ramirez for their letter (1) and for initiating further discussion of possible mechanisms underlying the effects of 4-1BB stimulation/deficiency on the obesity-induced responses of T cells/macrophages in adipose tissue (2,3), and how both conditions can lead to protection against metabolic complications.
Obesity-induced adipose inflammation is currently considered to create an optimal environment for autoimmune effects to take root (4). 4-1BB stimulation with agonistic anti–4-1BB antibody is known to attenuate many autoimmune inflammatory diseases by enhancing the expansion of regulatory T cells (Tregs) and hyperactivating γ-interferon (IFN-γ)–producing CD8+ Tregs (5). Our observations that IFN-γ (IFN-γ itself directly inhibits monocyte migration ) and interleukin (IL)-10 increase in response to 4-1BB stimulation (2) suggest that the anti–4-1BB antibody–induced Tregs suppress the obesity-induced pathogenic responses of inflammatory cells (Th1, CD8+ T cells, M1 macrophages) in a manner similar to the way they control autoimmune diseases, and this may ultimately lead to protection against metabolic disorders. Alternatively, it has become clear that the interaction of 4-1BB with 4-1BB ligand (4-1BBL) regulates various inflammatory processes in a bidirectional manner (7,8), and this often complicates the interpretation of experiments using agonistic anti–4-1BB antibody and/or 4-1BB deletion models (8). Macrophages express 4-1BBL, and 4-1BBL–mediated reverse signaling on macrophages promotes their proliferation and survival and causes them to release cytokines (8). Intriguingly, it is likely that agonistic anti–4-1BB antibody blocks the 4-1BBL–mediated inflammatory responses of 4-1BBL–expressing cells by disturbing the 4-1BB/4-1BBL interaction (9). Hence, 4-1BBL–mediated reverse signaling in adipose macrophages may be suppressed in conditions of both 4-1BB stimulation and deficiency, leading in each case to protecting obesity-induced inflammation and metabolic complications (2,3). As discussed previously (2,3), 4-1BB stimulation/deficiency differentially alters cellular responses of immune cells and enhances lipid/glucose metabolism. We suppose that there may be a relationship between 4-1BB/4-1BBL signaling and metabolic pathways, and this possibility is currently under investigation in our laboratory. Elucidation of the mechanisms underlying the effects of 4-1BB/4-1BBL signals on immunometabolism may provide clues to the link between inflammation and metabolism.
No potential conflicts of interest relevant to this article were reported.
- © 2012 by the American Diabetes Association.
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