Siglec-H is a DAP12-associated receptor on plasmacytoid dendritic cells (pDCs) and microglia. Siglec-H inhibits TLR9-induced IFN-α production by pDCs. Previously, it was found that Siglec-H-deficient mice develop a lupus-like severe autoimmune disease after persistent murine cytomegalovirus (mCMV) infection. This was due to enhanced type I interferon responses, including IFN-α. Here we examined, whether other virus infections can also induce autoimmunity in Siglec-H-deficient mice. To this end we infected Siglec-H-deficient mice with influenza virus or with Lymphocytic Choriomeningitis virus (LCMV) clone 13. With both types of viruses we did not observe induction of autoimmune disease in Siglec-H-deficient mice. This can be explained by the fact that both types of viruses are ssRNA viruses that engage TLR7, rather than TLR9. Also, Influenza causes an acute infection that is rapidly cleared and the chronicity of LCMV clone 13 may not be sufficient and may rather suppress pDC functions. Siglec-H inhibited exclusively TLR-9 driven type I interferon responses, but did not affect type II or type III interferon production by pDCs. Siglec-H-deficient pDCs showed impaired Hck expression, which is a Src-family kinase expressed in myeloid cells, and downmodulation of the chemokine receptor CCR9, that has important functions for pDCs. Accordingly, Siglec-H-deficient pDCs showed impaired migration towards the CCR9 ligand CCL25. Furthermore, autoimmune-related genes such as Klk1 and DNase1l3 are downregulated in Siglec-H-deficient pDCs as well. From these findings we conclude that Siglec-H controls TLR-9-dependent, but not TLR-7 dependent inflammatory responses after virus infections and regulates chemokine responsiveness of pDCs.
Copyright © 2021 Szumilas, Corneth, Lehmann, Schmitt, Cunz, Cullen, Chu, Marosan, Mócsai, Benes, Zehn, Dudziak, Hendriks and Nitschke.

Macrophages are multifunctional cells that are active in TH1- and TH2-mediated responses. In this study, we demonstrate that human and mouse macrophages collaborate with neutrophils and complement to kill the parasite Strongyloides stercoralis in vitro. Infection of mice with worms resulted in the induction of alternatively activated macrophages (AAM) within the peritoneal cavity. These cells killed the worms in vivo and collaborated with neutrophils and complement during the in vitro killing process. AAM generated in vitro killed larvae more rapidly than naive macrophages, which killed larvae after a longer time period. In contrast, classically activated macrophages were unable to kill larvae either in vitro or in vivo. This study adds macrophages to the armamentarium of immune components that function in elimination of parasitic helminths and demonstrate a novel function by which AAM control large extracellular parasites.

Increased remissions in multiple sclerosis (MS) during late pregnancy may result from high levels of sex steroids such as estrogen and estriol. Estrogen (E2=17β-estradiol) protects against experimental autoimmune encephalomyelitis (EAE), but the cellular basis for E2-induced protection remains unclear. Treatment with relatively low doses of E2 can protect against clinical and histological signs of MOG-35-55 induced EAE through mechanisms involving the PD-1 coinhibitory pathway and B-cells. The current study evaluated the contribution of PD-1 ligands, PD-L1 and PD-L2, on B-cells in E2-mediated protection against EAE in WT, PD-L1-/- and PD-L2-/- mice. Unlike PD-L2-/- mice that were fully protected against EAE after E2 treatment, E2-implanted PD-L1-/- mice were fully susceptible to EAE, with increased numbers of proliferating Th1/Th17 cells in the periphery and severe cellular infiltration and demyelination in the CNS. Moreover, transfer of B-cells from MOG-immunized PD-L1-/- or PD-L2-/- donors into E2-preconditioned B-cell deficient μMT-/- recipient mice revealed significantly reduced E2-mediated protection against EAE in recipients of PD-L1-/- B-cells, but near-complete protection in recipients of PD-L2-/- B-cells. We conclude that PD-1 interaction with PD-L1 but not PD-L2 on B-cells is crucial for E2-mediated protection in EAE and that strategies that enhance PD-1/PD-L1 interactions might potentiate E2 treatment effects in MS.

A sphingosine 1 phosphate receptor modulator, FTY720, has been used to alleviate symptoms in allotransplantation and autoimmune disease models with impressive efficacy, while it only achieved moderate success in clinical trials. Infusion of immature bone marrow-derived dendritic cell (BMDC) progenitors before transplantation could induce donor specific tolerance. In this study, we investigated the possibility of using FTY720-DCs (FTY720-treated immature BMDCs) to prevent severe alloimmune response. Our results indicate that FTY720-DCs could markedly prolong graft survival compared with Ctrl-DCs (nonconditioned immature BMDCs) as manifested by reduced inflammatory infiltration into the graft. IFN-γ production by CD4(+) and CD8(+) T cells were significantly reduced, while FoxP3(+) regulatory T cells among CD4(+) T cells were upregulated. Although FTY720 seldom altered the phenotype or the phagocytosis of BMDCs in vitro, it severely hampered their capability to trigger antigen-specific and allogeneic T-cell response. When splenic T cells were co-cultured with FTY720-DCs, the proportion of regulatory T cells increased, accompanied by elevated IL-10 production. Consistently, infusion of FTY720-DCs could preferentially promote Treg proliferation and upregulate PD-1 expression on conventional T cells in allogeneic mature BMDC priming experiment. These results suggest that infusion of FTY720-DCs before cardiac transplantation could significantly prolong functional graft survival by acting as a balancer of alloimmune response.
© 2010 The Authors. Journal compilation © 2010 European Society for Organ Transplantation.

Dendritic cells (DC) are able to capture, process, and present exogenous Ag to CD8(+) T lymphocytes through MHC class I, a process referred to as cross-presentation. In this study, we demonstrate that CD103(+) (CD11c(high)CD11b(low)) and CD103(-) (CD11c(int)CD11b(high)) DC residing in the lung-draining bronchial lymph node (brLN) have evolved to acquire opposing functions in presenting innocuous inhaled Ag. Thus, under tolerogenic conditions, CD103(-) DC are specialized in presenting innocuous Ag to CD4(+) T cells, whereas CD103(+) DC, which do not express CD8alpha, are specialized in presenting Ag exclusively to CD8(+) T cells. In CCR7-deficient but not in plt/plt mice, Ag-carrying CD103(+) DC are largely absent in the brLN, although CD103(+) DC are present in the lung of CCR7-deficient mice. As a consequence, adoptively transferred CD8(+) T cells can be activated under tolerizing conditions in plt/plt but not in CCR7-deficient mice. These data reveal that CD103(+) brLN DC are specialized in cross-presenting innocuous inhaled Ag in vivo. Because these cells are largely absent in CCR7(-/-) mice, our findings strongly suggest that brLN CD103(+) DC are lung-derived and that expression of CCR7 is required for their migration from the lung into its draining lymph node.