Leptin Modulates the Survival of Autoreactive CD4+ T Cells through the Nutrient/Energy-Sensing Mammalian Target of Rapamycin Signaling Pathway

Abstract

Chronic inflammation can associate with autoreactive immune responses, including CD4+ T cell responses to self-Ags. In this paper, we show that the adipocyte-derived proinflammatory hormone leptin can affect the survival and proliferation of autoreactive CD4+ T cells in experimental autoimmune encephalomyelitis, an animal model of human multiple sclerosis. We found that myelin olygodendrocyte glycoprotein peptide 35–55 (MOG35–55)-specific CD4+ T cells from C57BL/6J wild-type mice could not transfer experimental autoimmune encephalomyelitis into leptin-deficient ob/ob mice. Such a finding was associated with a reduced proliferation of the transferred MOG35–55-reactive CD4+ T cells, which had a reduced degradation of the cyclin-dependent kinase inhibitor p27kip1 and ERK1/2 phosphorylation. The transferred cells displayed reduced Th1/Th17 responses and reduced delayed-type hypersensitivity. Moreover, MOG35–55-reactive CD4+ T cells in ob/ob mice underwent apoptosis that associated with a downmodulation of Bcl-2. Similar results were observed in transgenic AND-TCR- mice carrying a TCR specific for the pigeon cytochrome c 88–104 peptide. These molecular events reveal a reduced activity of the nutrient/energy-sensing AKT/mammalian target of rapamycin pathway, which can be restored in vivo by exogenous leptin replacement. These results may help to explain a link between chronic inflammation and autoimmune T cell reactivity.

Selective capacity of metreleptin administration to reconstitute CD4 + T-cell number in females with acquired hypoleptinemia

“…These observations confirm that leptin administration promotes the expression of genes involved in pathways critical to cell survival, proliferation, and migration through transcriptional regulation (3,36). These observations also help explain leptin's marked ability to improve CD4 + T-cell survival and to promote immune reconstitution, perhaps suggesting an important role for leptin in the context of susceptibility to autoimmune disease (2).…”

Leptin-Induced mTOR Activation Defines a Specific Molecular and Transcriptional Signature Controlling CD4+ Effector T Cell Responses

“…Moreover, recent evidence showed that adipose tissue, through leptin, has a key role in the survival of autoreactive CD4 + T cells in vivo. It was found that leptin regulates the survival of autoantigen-specific CD4 + T cells directly through the activation of mTOR and the survival gene Bcl-2, as well as indirectly through the reduced secretion of cytokines important for autoreactive CD4 + T cell survival (IL-6, IL-15, IL-21, and GM-CSF) (29). In view of our recent findings that indicated hyperactivity of the leptin/mTOR pathway in Tregs …”

“…mTOR is activated in response to leptin, and rapamycin inhibits the anorexigenic effects of leptin. At the immune level, mTOR activity controls leptininduced activation of macrophages and the responsiveness of Tregs (9) and autoreactive T cell survival (29). Yet, the signaling events that lead to mTOR activation in effector CD4 + CD25 FOXP3 2 T cells (Teffs) are only partly understood (3); the same holds true for the ability of leptin to influence Teff responses.…”

Severe Disability in Patients with Relapsing-Remitting Multiple Sclerosis Is Associated with Profound Changes in the Regulation of Leptin Secretion

“…In patients with rheumatoid arthritis - a Th1-oriented chronic inflammatory disease - plasma leptin concentrations correlated inversely with the degree of inflammation [6]. Experimental evidences indicate that leptin can directly up-regulate both phagocytosis and the production of Th1-type pro-inflammatory cytokines [7,8,9,10] and modulates the survival and proliferation of autoreactive Th1/Th17 cells [11]. Leptin is also required for the induction and progression of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS) [12,13,14].…”