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Langerhans cell histiocytosis (LCH) is a rare neoplastic disorder characterized by inflammatory lesions arising from the anomalous accumulation of pathogenic CD1a⁺CD207⁺ dendritic cells (DCs). SIRPα is a transmembrane protein highly expressed in myeloid cells such as DCs and macrophages. Here we show that SIRPα is a potential therapeutic target for LCH. We found that SIRPα is expressed in CD1a⁺ cells of human LCH lesions as well as in CD11c⁺ DCs in the spleen, liver, and lung of a mouse model of LCH (BRAFV600ECD11c mouse), in which an LCH-associated active form of human BRAF is expressed in a manner dependent on the mouse Cd11c promoter. BRAFV600ECD11c mice manifested markedly increased numbers of CD4⁺ T cells, regulatory T cells, and macrophages as well as of CD11c⁺MHCII⁺ DCs in the spleen. Monotherapy with a mAb to SIRPα greatly reduced the percentage of CD11c⁺MHCII⁺ DCs in peripheral blood, LCH-like lesion size in the liver, and the number of CD11c⁺MHCII⁺ DCs in the spleen of the mutant mice. Moreover, this mAb promoted macrophage-mediated phagocytosis of CD11c⁺ DCs from BRAFV600ECD11c mice, whereas it had no effects on the viability or CCL19-dependent migration of such CD11c⁺ DCs or on their expression of the chemokine genes Ccl5, Ccl20, Cxcl11, and Cxcl12. Our results thus suggest that anti-SIRPα monotherapy is a promising approach to the treatment of LCH that is dependent in part on the promotion of the macrophage-mediated killing of LCH cells.

Signal regulatory protein α (SIRPα) is expressed predominantly on type 2 conventional dendritic cells (cDC2s) and macrophages. We previously showed that mice systemically lacking SIRPα were resistant to experimental autoimmune encephalomyelitis (EAE). Here, we showed that deletion of SIRPα in CD11c+ cells of mice (SirpaΔDC mice) also markedly ameliorated the development of EAE. The frequency of cDCs and migratory DCs (mDCs), as well as that of Th17 cells, were significantly reduced in draining lymph nodes of SirpaΔDC mice at the onset of EAE. In addition, we found the marked reduction in the number of Th17 cells and DCs in the CNS of SirpaΔDC mice at the peak of EAE. Whereas inducible systemic ablation of SIRPα before the induction of EAE prevented disease development, that after EAE onset did not ameliorate the clinical signs of disease. We also found that EAE development was partially attenuated in mice with CD11c+ cell-specific ablation of CD47, a ligand of SIRPα. Collectively, our results suggest that SIRPα expressed on CD11c+ cells, such as cDC2s and mDCs, is indispensable for the development of EAE, being required for the priming of self-reactive Th17 cells in the periphery as well as for the inflammation in the CNS.

Nonhematopoietic stromal cells contribute to the organization and homeostasis of secondary lymphoid organs by producing cytokines and chemokines. The development and maintenance of these stromal cells are thought to be regulated by innate immune cells. Indeed, we recently showed that signal regulatory protein α (SIRPα)-positive dendritic cells (DCs) are essential for the proliferation and survival of podoplanin (Pdpn)-positive fibroblastic reticular cells (FRCs) in mouse spleen. We have now established an in vitro culture system for lymph node stromal cells (LNSCs) isolated from mouse peripheral LNs. Activated DCs and TNF-α each promoted the proliferation of cultured LNSCs, most of which were found to be Pdpn(+) FRCs. Furthermore, ablation of SIRPα in CD11c(+) cells attenuated this effect of DCs on LNSC proliferation. Transplantation of activated DCs together with cultured LNSCs into the renal subcapsular space markedly increased the number of ER-TR7(+) stromal cells as well as induced the accumulation of T cells and increased the expression of Ccl19 in the transplants. Ablation of SIRPα in CD11c(+) cells greatly impaired the development of LN-like structure in the transplants. Our findings thus suggest that SIRPα+ DCs are important for the proliferation and differentiation of Pdpn(+) FRCs in peripheral LNs.

Simple Summary Recent studies revealed that type-2 conventional dendritic cells (cDC2s) play an important role in antitumor immunity by promoting cytotoxic T-cell responses and helper T-cell differentiation. This review outlines the role of cDC2s in tumor immunity and summarizes the latest progress regarding their potential in cancer vaccination and cDC2-targeted cancer immunotherapy. Conventional dendritic cells (cDCs) orchestrate immune responses to cancer and comprise two major subsets: type-1 cDCs (cDC1s) and type-2 cDCs (cDC2s). Compared with cDC1s, which are dedicated to the activation of CD8+ T cells, cDC2s are ontogenically and functionally heterogeneous, with their main function being the presentation of exogenous antigens to CD4+ T cells for the initiation of T helper cell differentiation. cDC1s play an important role in tumor-specific immune responses through cross-presentation of tumor-derived antigens for the priming of CD8+ T cells, whereas little is known of the role of cDC2s in tumor immunity. Recent studies have indicated that human cDC2s can be divided into at least two subsets and have implicated these cells in both anti- and pro-tumoral immune responses. Furthermore, the efficacy of cDC2-based vaccines as well as cDC2-targeted therapeutics has been demonstrated in both mouse models and human patients. Here we summarize current knowledge about the role of cDC2s in tumor immunity and address whether these cells are beneficial in the context of antitumor immune responses.

Nonhematopoietic stromal cells contribute to the organization and homeostasis of secondary lymphoid organs by producing cytokines and chemokines. The development and maintenance of these stromal cells are thought to be regulated by innate immune cells. Indeed, we recently showed that signal regulatory protein α (SIRPα)-positive dendritic cells (DCs) are essential for the proliferation and survival of podoplanin (Pdpn)-positive fibroblastic reticular cells (FRCs) in mouse spleen. We have now established an in vitro culture system for lymph node stromal cells (LNSCs) isolated from mouse peripheral LNs. Activated DCs and TNF-α each promoted the proliferation of cultured LNSCs, most of which were found to be Pdpn

Homeostasis of Pdpn+ fibroblastic reticular cells (FRCs) is thought to be regulated by hematopoietic cells. However, the cellular and molecular mechanisms of such homeostasis have been poorly understood, especially under the steady-state condition in adults. We show that dendritic cells, particularly CD4+ conventional dendritic cells (cDCs), are crucial for the homeostasis of FRCs in the adult spleen under the steady-state condition. The production of TNF receptor ligands by CD4+ cDCs regulates such homeostasis of FRCs, with SIRPα and CD47 likely being indispensable for the production of TNFR ligands by CD4+ cDCs. The CD47–SIRPα interaction on CD4+ cDCs may thus control the homeostasis of FRCs, which in turn maintain homeostasis of T cells in the white pulp of the spleen.