In vivo transformation of mouse conventional CD8α+ dendritic cells leads to progressive multisystem histiocytosis

Abstract

IntroductionDendritic cells (DCs) are the antigen-presenting cells (APCs) capable of inducing adaptive immune responses and tolerance. 1 DCs act as sentinels in peripheral tissues and as APCs in secondary lymphoid organs, filtering their environment and detecting environmental changes that modulate the balance between tolerance and immune response. Following infection and inflammation, DCs induce costimulatory molecules, secrete cytokines, and can change their migration properties. 2,3 Several DC subtypes with unique and overlapping functions have been described. Plasmacytoid DCs (pDCs) are the main interferon (IFN) type I-producing cells, whereas several subtypes of conventional DCs (cDCs) are widely distributed. 4,5 In skin, 2 DC populations, namely Langerhans cells (LCs) and dermal DCs, localize to the epidermis and dermis, respectively. Upon pathogen encounter, they migrate to the draining LN. 6 In skin and spleen, DCs are derived either from blood or from immediate local precursors. [7][8][9][10][11][12][13] DCs are dividing cells rather than terminally differentiated cells. [12][13][14][15] The importance of DC cycling on their homeostasis is currently debated, and DC proliferation has been recently proposed to extend the duration of antigen presentation. 15 The human histiocytic diseases are characterized by abnormal accumulation or proliferation of macrophages or DCs. 16 They are divided into LC or non-LC histiocytosis. In the former category, LC histiocytosis (LCH) is best described. LCH can range from a spontaneously regressing single organ disease to a life-threatening or disabling relapsing multisystem disease. 16 In the latter category, a genetic deficiency in cytotoxic activity, familial hemophagocytic lymphohistiocytosis (FHL), is the principal type implicating macrophages and lymphocytes. In contrast to LCH and FHL, lesions with proliferative DCs with or without cytologic atypia are less well classified and their prevalence remains controversial. 16 Unfortunately, a confusing terminology describing these cases of proliferating DCs persists in the literature as malignant histiocytosis, histiocytic sarcoma, and DC sarcoma.The diagnosis of histiocytic diseases relies on the morphologic, ultrastructural, and immunohistochemical histiocyte properties. The macrophage, DC, or LC lineage markers allow LC to be distinguished from non-LC histiocytosis. For example, diagnostic criteria for LCH include expression of Langerin or detection of Birbeck granules that are pathognomonic, as well as CD1a and S100, which are less specific. According to the International Lymphoma Study Group, histiocytic sarcoma, LC tumor, and LC sarcoma (LCS) are the terms used to separate cases based on the degree of cytologic atypia and on lineage markers. 17 For example, diagnosis of LCS requires the same markers as LCH and the additional presence of cellular and mitotic atypia.While LCS, LC, and DC tumors are clearly neoplastic, it is vigorously debated whether LCH is a reactive or a neoplastic The online version of this article ...

Langerin+CD8α+ Dendritic Cells Are Critical for Cross-Priming and IL-12 Production in Response to Systemic Antigens

“…Since murine Clec9A ϩ cells and langerin ϩ CD8␣ ϩ DC have been shown to be related functionally in terms of capacity to cross-present cell-associated Ags, it will be interesting to determine whether a Clec9A ϩ BDCA3 ϩ DC population with similar function is located within the marginal zones of human spleen. The langerin molecule itself has recently been shown to be expressed in human spleen, although in the T cell zone rather than marginal zone (60). Langerin ϩ cells can also be detected in other human tissues such as lymph nodes, gut, lung epithelium (61), and kidney (62); whether any of these populations represents a non-LC langerin ϩ cell type with similar function to murine langerin ϩ CD8␣ ϩ DC remains to be determined.…”

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