Pro-opiomelanocortin (POMC)-derived peptides (the melanocortins adrenocorticotropin, alpha-, beta- and gamma-melanocyte stimulating hormone; and the endogenous opioid beta-endorphin) have a diverse array of biological activities, including roles in pigmentation, adrenocortical function and regulation of energy stores, and in the immune system and the central and peripheral nervous systems. We show here that mice lacking the POMC-derived peptides have obesity, defective adrenal development and altered pigmentation. This phenotype is similar to that of the recently identified human POMC-deficient patients. When treated with a stable alpha-melanocyte-stimulating hormone agonist, mutant mice lost more than 40% of their excess weight after 2 weeks. Our results identify the POMC-null mutant mouse as a model for studying the human POMC-null syndrome, and indicate the therapeutic use of peripheral melanocortin in the treatment of obesity.

The development of T cells in the thymus is coordinated by cell-specific gene expression programs that involve multiple transcription factors and signaling pathways. Here, we show that the p38 mitogen-activated protein (MAP) kinase signaling pathway is strictly regulated during the differentiation of CD4−CD8− thymocytes. Persistent activation of p38 MAP kinase blocks fetal thymocyte development at the CD25+CD44− stage in vivo, and results in the lack of T cells in the peripheral immune system of adult mice. Inactivation of p38 MAP kinase is required for further differentiation of these cells into CD4+CD8+ thymocytes. The arrest of cell cycle in mitosis is partially responsible for the blockade of differentiation. Therefore, the p38 MAP kinase pathway is a critical regulatory element of differentiation and proliferation during the early stages of in vivo thymocyte development.

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CD4؉ and CD8 ؉ T cells play specific roles during an immune response. Different molecular mechanisms could regulate the proliferation, death, and effector functions of these two subsets of T cells. The p38 mitogen-activated protein (MAP) kinase pathway is induced by cytokines and environmental stress and has been associated with cell death and cytokine expression. Here we report that activation of the p38 MAP kinase pathway in vivo causes a selective loss of CD8 ؉ T cells due to the induction of apoptosis. In contrast, activation of p38 MAP kinase does not induce CD4 ؉ T-cell death. The apoptosis of CD8 ؉ T cells is associated with decreased expression of the antiapoptotic protein Bcl-2. Regulation of the p38 MAP kinase pathway in T cells is therefore essential for the maintenance of CD4/CD8 homeostasis in the peripheral immune system. Unlike cell death, gamma interferon production is regulated by the p38 MAP kinase pathway in both CD4؉ and CD8 ؉ T cells. Thus, specific aspects of CD4 ؉ and CD8 ؉ T-cell function are differentially controlled by the p38 MAP kinase signaling pathway. CD4ϩ and CD8 ϩ T cells perform distinct functions to mediate the immune response. The commitment of CD4 and CD8 lineages occurs during T-cell development in the thymus, and it is maintained throughout the life spans of the T cells in the peripheral immune system. CD4 ϩ CD8 ϩ double-positive (DP) thymocytes differentiate into mature CD4 ϩ or CD8 ϩ thymocytes depending on the respective T-cell receptor (TCR) specificity for major histocompatibility complex (MHC) class II or class I, respectively (positive selection). Mature CD4 ϩ and CD8 ϩ thymocytes leave the thymus and migrate to the peripheral immune system, becoming naive CD4 ϩ and CD8 ϩ T cells. Although both CD4 ϩ and CD8 ϩ T cells undergo clonal expansion in response to antigens, naive CD4 ϩ T cells differentiate into helper effector cells while naive CD8 ϩ T cells become cytotoxic cells. Effector CD4 ϩ T cells rapidly produce large amounts of cytokine in response to an antigen. While CD8 ϩ T cells can also secrete cytokines (e.g., gamma interferon [IFN-␥]), their major role in the immune response appears to be cytotoxic activity, mediated by secreted proteins, such as perforin and granzyme.The divergent functions of CD4 ϩ and CD8 ϩ T cells suggest that distinct signaling requirements and molecular mechanisms could mediate the activation of each subset in response to antigens or environmental stimuli. Several examples of these differential controls have been described. Costimulations through 4-1BB (a new member of the tumor necrosis factor [TNF] receptor family) and CD28 are complementary to one another by activating CD8 ϩ and CD4 ϩ T cells, respectively (49). Signaling through the Fas ligand appears to be required for CD8 ϩ T-cell proliferation but not for CD4 ϩ T-cell proliferation (52).The numbers of CD4 ϩ and CD8 ϩ cells in the periphery remain constant under normal conditions, but the presence of specific pathological environments can modulate the CD4/ CD8 homeostasis by pre...