We report here that leptin can act as a negative signal for the proliferation of human naturally occurring Foxp3(+)CD4(+)CD25(+) regulatory T (T(reg)) cells. Freshly isolated T(reg) cells produced leptin and expressed high amounts of leptin receptor (ObR). In vitro neutralization with leptin monoclonal antibody (mAb), during anti-CD3 and anti-CD28 stimulation, resulted in T(reg) cell proliferation, which was interleukin-2 (IL-2) dependent. T(reg) cells that proliferated in the presence of leptin mAb had increased expression of Foxp3 and remained suppressive. The phenomena appeared secondary to leptin signaling via ObR and, importantly, leptin neutralization reversed the anergic state of the T(reg) cells, as indicated by downmodulation of the cyclin-dependent kinase inhibitor p27 (p27(kip1)) and the phosphorylation of the extracellular-related kinases 1 (ERK1) and ERK2. Together with the finding of enhanced proliferation of T(reg) cells observed in leptin- and ObR-deficient mice, these results suggest a potential for therapeutic interventions in immune and autoimmune diseases.

Recent evidence indicates that leptin modifies T cell immunity, and may provide a key link between nutritional deficiency and immune dysfunction. To study the influence of leptin on autoimmunity, susceptibility to experimental autoimmune encephalomyelitis induced by immunization with a myelin-derived peptide was examined in leptin-deficient, C57BL/6J-ob/ob mice, with or without leptin replacement, and in wild-type controls. Leptin replacement converted disease resistance to susceptibility in the C57BL/6J-ob/ob mice; this was accompanied by a switch from a Th2 to Th1 pattern of cytokine release and consequent reversal of Ig subclass production. Our findings suggest that leptin is required for the induction and maintenance of an effective proinflammatory immune response in the CNS.

autoimmunity ͉ tolerance ͉ metabolism ͉ hormones I t has recently been shown that leptin, a cytokine-like hormone mainly secreted by adipocytes, can play a significant role in the pathogenesis of several autoimmune diseases, such as experimental autoimmune encephalomyelitis (EAE), antigen-induced arthritis, and experimentally induced colitis (1-6). EAE is an animal model for the human demyelinating disease multiple sclerosis (MS) (7,8). EAE can be induced in susceptible strains of mice through immunization with myelin antigens or by adoptive transfer of myelinspecific T helper 1 (Th-1) cells (7,8). Genetically leptin-deficient (ob͞ob) mice are resistant to the induction and progression of EAE, and WT EAE-susceptible mice show an increase in serum leptin preceding the clinical onset of the disease that correlates with inflammatory anorexia and disease susceptibility (2, 3). In addition, pathogenic Th-1 cells and macrophages in active EAE brain lesions secrete consistent amounts of leptin (3). These data account for an involvement of leptin in CNS autoimmunity, at least in the EAE model. Despite this finding, in humans, the role of leptin in the pathogenesis of MS is not yet fully elucidated. In this study, we analyzed the secretion of leptin in the cerebrospinal fluid (CSF) and serum of naïve-to-treatment relapsing-remitting MS (RRMS) patients and leptin's interaction with the CD4 ϩ CD25 ϩ regulatory T cells (T Regs ). T Regs are known to dampen autoreactive responses mediated by CD4 ϩ CD25 Ϫ T cells and may influence the onset and progression of autoimmunity (9). In mice, depletion of T Regs is associated with autoimmunity, and defects of T Regs have been described in nonobese diabetic mice and in humans with type 1 diabetes (9, 10). Also, reduced frequency of T Regs and͞or defective suppressor function have been observed in humans with systemic lupus erythematosus, juvenile idiopathic arthritis, autoimmune polyglandular syndrome type II, and RRMS (11-15). T Regs are anergic in vitro but can expand in vivo (9). Although the mechanisms operated by T Regs in suppression are not fully delineated, the forkhead transcription factor FoxP-3 seems to be required for suppression to occur (9).Here, we report increased leptin levels in CSF and serum of naïve-to-therapy RRMS patients and an inverse correlation with T Regs frequency. These findings may be relevant in better understanding the disease pathogenesis and may have therapeutic implications. Materials and MethodsSubjects. All MS patients and controls were recruited at the Università di Napoli ''Federico II.'' For serum and CSF leptin measurement, we included in the study 126 individuals (Table 1) with MS defined according to the criteria of McDonald et al. (16) and 117 age-, gender-, and body mass index (BMI)-matched controls with other noninf lammatory neurologic disorders (NIND). All MS patients had RRMS and an expanded disability status scale score of Յ3.5 and were naïve to treatment. The inclusion criteria for RRMS patients were (i) onset of relapse within 4 w...

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