A key role of leptin in the control of regulatory T cell proliferation.
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.
De Rosa
Veronica
V
Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), 80131 Napoli, Italy.
Procaccini
Claudio
C
Calì
Gaetano
G
Pirozzi
Giuseppe
G
Fontana
Silvia
S
Zappacosta
Serafino
S
La Cava
Antonio
A
Matarese
Giuseppe
G
D000818:Animals; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D017635:Clonal Anergy; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology / Q000378:metabolism; D020738:Leptin / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D011956:Receptors, Cell Surface / Q000276:immunology / Q000378:metabolism; D054411:Receptors, Leptin; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007376:Interleukin-2; C515448:LEPR protein, human; D020738:Leptin; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; C515447:leptin receptor, mouse