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Recent studies highlight surprising roles for granulocyte-macrophage colony-stimulating factor (GM-CSF) production by T cells. T-cell-derived GM-CSF is required for the differentiation of monocyte-derived inflammatory dendritic cells during inflammation and for the pathogenicity of IL-17 producing T helper cells in autoimmunity. To gain further insight into these findings, we engineered in vivo overexpression of GM-CSF specifically in T cells, under the control of the Lck promoter. Lck-GM-CSF transgenic mice displayed a dramatic phenotype, characterized by splenomegaly, lymphadenopathy, thymic atrophy, and multiple abnormalities in blood cell populations. Thymocyte differentiation was severely affected, and there was a dramatic increase in regulatory T cells in the thymus and peripheral lymphoid organs. Lck-GM-CSF transgenic mice developed a disseminated histiocytosis and had increased circulating IL-17 producing T helper cells-related cytokines. The pathological characteristics in Lck-GM-CSF transgenic mice resemble those of histiocytic human diseases, such as Langerhans cell histiocytosis. The etiology of many histiocytic disorders is unknown, but our findings suggest that over-production of GM-CSF by T cells could be a pathogenic factor and raise the possibility that GM-CSF may represent a novel therapeutic target., (Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Originally implicated in axon guidance, semaphorins represent a large family of molecules that are now known to be expressed in the immune system. Among different semaphorins tested by reverse transcriptase-polymerase chain reaction in human immune cells, the expression of class 6 transmembrane semaphorin SEMA6A was restricted to dendritic cells (DCs). Using in-house generated monoclonal antibodies, SEMA6A expression appeared further restricted to Langerhans cells (LCs). In vivo, SEMA6A mRNA was expressed in freshly isolated skin LCs but SEMA6A protein was not detectable on normal skin and tonsillar epithelium. Of interest, SEMA6A protein was strongly expressed on skin and bone LCs and on LCs in draining lymph nodes from patients with LC histiocytosis or dermatopathic lymphadenitis, respectively, representing two inflammatory conditions in which LCs display an immature DC-LAMP(low), CD83(low), and CCR7+ phenotype. SEMA6A expression was low in resting LCs generated in vitro and was enhanced by interferon (IFN)-gamma but not by interleukin-4, interleukin-10, IFN-alpha/beta, or lipopolysaccharide. Most IFN-gamma-induced SEMA6A-positive cells remained immature with low CD83 and DC-LAMP/CD208 expression, but they expressed CCR7 and responded to macrophage inflammatory protein-3beta (MIP-3beta/CCL19). The expression of SEMA6A, for which the ligand and function remain unknown, may therefore identify an alternative IFN-gamma-dependent activation status of LCs in vivo.