Highlights d RPMs are embedded in a meshwork of WT1, CSF1expressing RP fibroblasts d RP fibroblasts represent a unique subset of splenic stromal cells d RP-fibroblast-derived CSF1 controls homeostasis of RPMs d RP fibroblasts participate to the recruitment of monocytes

Multiple Inflammatory Syndrome in Children (MIS-C) is a delayed and severe complication of SARS-CoV-2 infection that strikes previously healthy children. As MIS-C combines clinical features of Kawasaki disease and Toxic Shock Syndrome (TSS), we aimed to compare the immunological profile of pediatric patients with these different conditions. We analyzed blood cytokine expression, and the T cell repertoire and phenotype in 36 MIS-C cases, which were compared to 16 KD, 58 TSS, and 42 COVID-19 cases. We observed an increase of serum inflammatory cytokines (IL-6, IL-10, IL-18, TNF-α, IFNγ, CD25s, MCP1, IL-1RA) in MIS-C, TSS and KD, contrasting with low expression of HLA-DR in monocytes. We detected a specific expansion of activated T cells expressing the Vβ21.3 T cell receptor β chain variable region in both CD4 and CD8 subsets in 75% of MIS-C patients and not in any patient with TSS, KD, or acute COVID-19; this correlated with the cytokine storm detected. The T cell repertoire returned to baseline within weeks after MIS-C resolution. Vβ21.3+ T cells from MIS-C patients expressed high levels of HLA-DR, CD38 and CX3CR1 but had weak responses to SARS-CoV-2 peptides in vitro. Consistently, the T cell expansion was not associated with specific classical HLA alleles. Thus, our data suggested that MIS-C is characterized by a polyclonal Vβ21.3 T cell expansion not directed against SARS-CoV-2 antigenic peptides, which is not seen in KD, TSS and acute COVID-19.

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Located in the abdominal cavity between the diaphragm and the fundus of the stomach, the spleen is the largest secondary lymphoid organ in the body. It acts mainly as a blood filter that selectively removes immune complexes, circulating pathogens and senescent, dysfunctional, or infected red blood cells. 1 As a result, splenectomy is associated with an increased susceptibility to severe bacterial infections (Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis…) and a major risk of overwhelming sepsis. 2,3 Besides its immune function, the spleen is involved in other important physiological processes such as iron homeostasis. Senescent or ruptured red blood cells are trapped in the spleen and their hemoglobin content is metabolized into free iron, which supplies most of the iron needed for erythropoiesis. 4,5 The adult spleen is also a prominent site for extramedullary hematopoiesis. In conditions of infection, anemia and genetic blood disorders or during pregnancy, hematopoietic stem cells (HSC) mobilized from the bone marrow

Type I and III interferons (IFN-I/λ) are important antiviral mediators against SARS-CoV-2 infection. Here, we demonstrate that plasmacytoid dendritic cells (pDC) are the predominant IFN-I/λ source following their sensing of SARS-CoV-2-infected cells. Mechanistically, this short-range sensing by pDCs requires sustained integrin-mediated cell adhesion with infected cells. In turn, pDCs restrict viral spread by an IFN-I/λ response directed toward SARS-CoV-2-infected cells. This specialized function enables pDCs to efficiently turn-off viral replication, likely via a local response at the contact site with infected cells. By exploring the pDC response in SARS-CoV-2 patients, we further demonstrate that pDC responsiveness inversely correlates with the severity of the disease. The pDC response is particularly impaired in severe COVID-19 patients. Overall, we propose that pDC activation is essential to control SARS-CoV-2-infection. Failure to develop this response could be important to understand severe cases of COVID-19.

Type I and III interferons (IFN-I/λ) are key antiviral mediators against SARS-CoV-2 infection. Here, we demonstrate that the plasmacytoid dendritic cells (pDCs) are predominant IFN-I/λ source by sensing SARS-CoV-2-infected cells. We show that sensing of viral RNA by pDCs requires sustained cell adhesion with infected cells. In turn, the pDCs restrict viral spread by a local IFN-I/λ response directed toward SARS-CoV-2-infected cells. This specialized function enables pDCs to efficiently turn-off viral replication, likely by a concentrated flux of antiviral effectors at the contact site with infected cells. Therefore, we propose that pDC activation is essential to locally control SARS-CoV-2-infection. By exploring the pDC response in patients, we further demonstrate that pDC responsiveness correlates with the severity of the disease and in particular that it is impaired in severe COVID-19 patients. Thus, the ability of pDCs to respond to SARS-CoV-2-infected cells could be a key to understand severe cases of COVID-19.

Multiple Inflammatory Syndrome in Children (MIS-C) is the most severe pediatric form of COVID-19 and occurs in previously healthy children. MIS-C combines features of Kawasaki disease and Toxic Shock Syndrome (TSS). We characterized the immunological profile of 27 MIS-C cases in comparison with 4 KD and 4 TSS cases. Similarly to TSS, an increase of serum inflammatory cytokines (IL-6, TNF-a, CD25s) was observed in MIS-C contrasting with low expression of HLA-DR monocytes, a feature often associated with immune paralysis. Expansions of T cells expressing the Vβ21.3 T cell receptor β chain variable region were detected in both CD4 and CD8 subsets in almost 50% of patients and Vβ21.3-positive T cells expressed high level of HLA-DR highlighting their specific activation. TCR sequencing uncovered the polyclonal nature of the Vβ 21.3+ population. SARS-CoV2 antigene-specific production of interferon gamma in T cells was not increased in MIS-C T cells compared to COVID-19 patients suggesting the antigen-specific immune response in MIS-C patients is not pivotal to the manifestation. Together, these data argue in favor of a strong activation of the immune system related to a superantigenic immune response in MIS-C with a specific polyclonal Vβ21.3 expressing T cell activation.

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