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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Abstract

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.

Tipologia di documento:Tesi di dottorato
Parole chiave:Leptin, T cells and Survival
Settori scientifico-disciplinari MIUR:Area 06 Scienze mediche > MED/04 PATOLOGIA GENERALE
Coordinatori della Scuola di dottorato:
Coordinatore del Corso di dottoratoe-mail (se nota)
Avvedimento, Vittorio Enrico
Tutor della Scuola di dottorato:
Tutor del Corso di dottoratoe-mail (se nota)
Avvedimento, Vittorio Enrico
Stato del full text:Accessibile
Data:27 Novembre 2009
Numero di pagine:55
Istituzione:Università degli Studi di Napoli Federico II
Dipartimento o Struttura:Biologia e Patologia Cellulare e Molecolare "Luigi Califano"
Tipo di tesi:Dottorato
Stato dell'Eprint:Inedito
Scuola di dottorato:Medicina Molecolare
Denominazione del dottorato:Patologia e Fisiopatologia Molecolare
Ciclo di dottorato:XXII
Numero di sistema:3952
Depositato il:28 Maggio 2010 14:27
Ultima modifica:13 Luglio 2012 11:17

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