Role of Leptin and metabolism in survival of autoreactive CD4+ T cells
Galgani, Mario (2009) Role of Leptin and metabolism in survival of autoreactive CD4+ T cells. [Tesi di dottorato] (Inedito)
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Recent evidence has shown that leptin, the adipose-tissue derived hormone, can influence T cell homeostasis and survival through the control of genes involved in these processes. Leptin deficient ob/ob mice and humans show reduced circulating number of T cells particularly in the CD4+ compartment. Here, we investigate in vivo how leptin controls survival and proliferation of normal and autoreactive CD4+ T cells. We have previously observed the impaired capacity of myelin-olygodendrocyte glycoprotein peptide (MOG35-55)-specific CD4+ T cells, to transfer experimental autoimmune encephalomyeleitis (EAE) in ob/ob mice. In vivo this process was associated with a progressive decline in dalyed-type hypersensitivity responses (DTH) and proliferation against the MOG35-55 peptide. Adoptive transfer experiments with pathogenic-MOG35-55-activated CD4+ T cells labeled with the fluorescent die 5-6-carboxyfluorescein succinimidylester (CFSE) into normal wild-type (WT), ob/ob and ob/ob-recombinant leptin (rleptin) treated mice, showed in ob/ob mice a reduction of the number of CFSE+CD4+ T cells at different time points as well as increased apoptosis rate and reduced Bcl-2 expression. Similar results were obtained after transferring into ob/ob mice homogeneous, antigen-specific T cells from pigeon cytochrome c (PCC) transgenic (AND-TCR) mice. Next, we explored the molecular targets possibly involved in this process and concentrated our attention on the AKT-mammalian-target of rapamycin (mTOR) signaling pathway. We observed a reduced expression of the AKT and of the downstream mTOR target, S6 ribonuclear protein (S6), in MOG35-55-specific T cells transferred into ob/ob mice. The involvement of the mTOR pathway was also confirmed by a reduced survival of the CD4+ T cells in WT mice after treatment with rapamycin and subsequent reduction in circulating leptin levels. These data highlight the role of leptin in the regulation of survival and proliferation of autoreactive T cells and link the metabolism to autoimmunity.
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