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* Department of Pathology and Immunology and
Department of Cellular Physiology and Metabolism, University of Geneva School of Medicine, Geneva, Switzerland;
Division of Rheumatology and
Department of Dermatology, Louis-Jeantet Skin Cancer Laboratory, University Hospital, Geneva, Switzerland; and
¶ Department of Medicine, Division of Rheumatology, University Hospital, Lausanne, Switzerland
Leptin-deficient ob/ob and leptin receptor (Ob-rb)-deficient db/db mice display a marked thymic atrophy and exhibit defective immune responses. Lymphocytes express leptin receptors and leptin exerts direct effects on T cells in vitro. In addition, ob/ob and db/db mice display multiple neuroendocrine and metabolic defects, through which leptin deficiency may indirectly affect the immune system in vivo. To study the relative contributions of direct and indirect effects of leptin on the immune system in a normal environment, we generated bone marrow chimeras (BMCs) by transplantation of leptin receptor-deficient db/db, or control db/+, bone marrow cells into wild-type (WT) recipients. The size and cellularity of the thymus, as well as cellular and humoral immune responses, were similar in db/db to WT and db/+ to WT BMCs. The immune phenotype of db/db mice is thus not explained by a cell autonomous defect of db/db lymphocytes. Conversely, thymus weight and cell number were decreased in the reverse graft setting in WT to db/db BMCs, indicating that expression of the leptin receptor in the environment is important for T cell development. Finally, normal thymocyte development occurred in fetal db/db thymi transplanted into WT hosts, indicating that direct effects of leptin are not required locally in the thymic microenvironment. In conclusion, direct effects of leptin on bone marrow-derived cells and on thymic stromal cells are not necessary for T lymphocyte maturation in normal mice. In contrast, leptin receptor deficiency affects the immune system indirectly via changes in the systemic environment.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Jean and Linette Warnery Foundation, the de Reuter Foundation, the Academic Society of Geneva, and the Swiss National Science Foundation (Grant 3200–107592/1 to C.G.; 3100–067896.02 to M.A.L.; and 310000–112551 to N.B.).
2 Address correspondence and reprint requests to Dr. Cem Gabay, Division of Rheumatology, University Hospital, 26 av. Beau-Séjour, 1211 Geneva 14, Switzerland. E-mail address: Cem.Gabay{at}hcuge.ch
3 Abbreviations used in this paper: BMC, bone marrow chimera; WT, wild type, LN, lymph node; DN, double negative; DP, double positive; mBSA, methylated BSA; AU, arbitrary units.
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