Major alterations in the mononuclear phagocyte landscape associated with COVID-19 severity.

Dendritic cells (DCs) and monocytes are crucial mediators of innate and adaptive immune responses during viral infection, but misdirected responses by these cells may contribute to immunopathology. Here, we performed high-dimensional flow cytometry-analysis focusing on mononuclear phagocyte (MNP) lineages in SARS-CoV-2-infected patients with moderate and severe COVID-19. We provide a deep and comprehensive map of the MNP landscape in COVID-19. A redistribution of monocyte subsets toward intermediate monocytes and a general decrease in circulating DCs was observed in response to infection. Severe disease coincided with the appearance of monocytic myeloid-derived suppressor cell-like cells and a higher frequency of pre-DC2. Furthermore, phenotypic alterations in MNPs, and their late precursors, were cell-lineage-specific and associated either with the general response against SARS-CoV-2 or COVID-19 severity. This included an interferon-imprint in DC1s observed in all patients and a decreased expression of the coinhibitory molecule CD200R in pre-DCs, DC2s, and DC3 subsets of severely sick patients. Finally, unsupervised analysis revealed that the MNP profile, alone, pointed to a cluster of COVID-19 nonsurvivors. This study provides a reference for the MNP response to SARS-CoV-2 infection and unravels mononuclear phagocyte dysregulations associated with severe COVID-19.

Combination of Mycobacterium indicus pranii and Heat-Induced Promastigotes Cures Drug-Resistant Leishmania Infection: Critical Role of Interleukin-6-Producing Classical Dendritic Cells.

The major issues in available therapeutic modalities against leishmaniasis are cost, toxicity, and the emergence of drug resistance. The aim of this work was to develop a successful therapeutic adjuvant against drug-resistant Leishmania donovani infection by means of combining Mycobacterium indicus pranii with heat-induced promastigotes (HIP). One-month postinfected BALB/c mice were administered subcutaneously with M. indicus pranii (108 cells) and HIP (100 µg) for 5 days. Spleens were harvested for flow cytometric and reverse transcriptase PCR analysis. The antileishmanial effect of the combination strategy was associated with induction of a disease-resolving Th1 and Th17 response with simultaneous downregulation of CD4+ CD25+ Foxp3+ (nTreg) cells and CD4+ CD25- Foxp3- (Tr1) cells in the spleen. The significant expansion of CD4+ TCM (CD4+ CD44hi CD11ahi CD62Lhi) cells was a further interesting outcome of this therapeutic strategy in the context of long-term protection of hosts against secondary infection. Toll-like receptor 2 (TLR2) was also found instrumental in this antiparasitic therapy. Induced interleukin-6 (IL-6) production from expanded CD11c+ CD8α+ (cDC1) and CD11c+ CD11b+ (cDC2) dendritic cells (DCs) but not from the CD11b+ Ly6c+ inflammatory monocytes (iMOs), was found critical in the protective expansion of Th17 as evidenced by an in vivo IL-6 neutralization assay. It also promoted the hematopoietic conversion toward DC progenitors (pre-DCs) from common dendritic cell progenitors (CDPs), the immediate precursors, in bone marrow. This novel combinational strategy demonstrated that expansion of Th17 by IL-6 released from CD11c+ classical DCs is crucial, together with the conventional Th1 response, to control drug-resistant infection.

Integrated Cross-Species Analysis Identifies a Conserved Transitional Dendritic Cell Population.

Plasmacytoid dendritic cells (pDCs) are sensor cells with diverse immune functions, from type I interferon (IFN-I) production to antigen presentation, T cell activation, and tolerance. Regulation of these functions remains poorly understood but could be mediated by functionally specialized pDC subpopulations. We address pDC diversity using a high-dimensional single-cell approach: mass cytometry (CyTOF). Our analysis uncovers a murine pDC-like population that specializes in antigen presentation with limited capacity for IFN-I production. Using a multifaceted cross-species comparison, we show that this pDC-like population is the definitive murine equivalent of the recently described human AXL+ DCs, which we unify under the name transitional DCs (tDCs) given their continuum of pDC and cDC2 characteristics. tDCs share developmental traits with pDCs, as well as recruitment dynamics during viral infection. Altogether, we provide a framework for deciphering the function of pDCs and tDCs during diseases, which has the potential to open new avenues for therapeutic design.

Distinct functions of CXCR4, CCR2, and CX3CR1 direct dendritic cell precursors from the bone marrow to the lung.

Precursors of dendritic cells (pre-DCs) arise in the bone marrow (BM), egress to the blood, and finally migrate to peripheral tissue, where they differentiate to conventional dendritic cells (cDCs). Upon their activation, antigen-bearing cDCs migrate from peripheral tissue to regional lymph nodes (LNs) in a manner dependent on the chemokine receptor, CCR7. To maintain immune homeostasis, these departing cDCs must be replenished by new cDCs that develop from pre-DCs, but the molecular signals that direct pre-DC trafficking from the BM to the blood and peripheral tissues remain poorly understood. In the present study, we found that pre-DCs express the chemokine receptors CXCR4, CCR2, and CX3CR1, and that each of these receptors has a distinct role in pre-DC trafficking. Flow cytometric analysis of pre-DCs lacking CXCR4 revealed that this receptor is required for the retention of pre-DCs in the BM. Analyses of mice lacking CCR2 or CX3CR1, or both, revealed that they promote pre-DC migration to the lung at steady state. CCR2, but not CX3CR1, was required for pre-DC migration to the inflamed lung. Thus, these multiple chemokine receptors cooperate in a step-wise fashion to coordinate the trafficking of pre-DCs from the BM to the circulation and peripheral tissues.