The COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and has spread worldwide, with millions of cases and more than 1 million deaths to date. The gravity of the situation mandates accelerated efforts to identify safe and effective vaccines. Here, we generated measles virus (MeV)-based vaccine candidates expressing the SARS-CoV-2 spike glycoprotein (S). Insertion of the full-length S protein gene in two different MeV genomic positions resulted in modulated S protein expression. The variant with lower S protein expression levels was genetically stable and induced high levels of effective Th1-biased antibody and T cell responses in mice after two immunizations. In addition to neutralizing IgG antibody responses in a protective range, multifunctional CD8+ and CD4+ T cell responses with S protein-specific killing activity were detected. Upon challenge using a mouse-adapted SARS-CoV-2, virus loads in vaccinated mice were significantly lower, while vaccinated Syrian hamsters revealed protection in a harsh challenge setup using an early-passage human patient isolate. These results are highly encouraging and support further development of MeV-based COVID-19 vaccines.
Interleukin-38 (IL-38) is a cytokine of the IL-1 family with a role in chronic inflammation. However, its main cellular targets and receptors remain obscure. IL-38 is highly expressed in the skin and downregulated in psoriasis patients. We report an investigation in cellular targets of IL-38 during the progression of imiquimod-induced psoriasis. In this model, IL-38 knockout (IL-38 KO) mice show delayed disease resolution with exacerbated IL-17-mediated inflammation, which is reversed by the administration of mature IL-38 or gd T cell-receptor-blocking antibodies. Mechanistically, X-linked IL-1 receptor accessory protein-like 1 (IL1RAPL1) is upregulated upon gd T cell activation to feedforward-amplify IL-17 production and is required for IL-38 to suppress gd T cell IL-17 production. Accordingly, psoriatic IL1RAPL1 KO mice show reduced inflammation and IL-17 production by gd T cells. Our findings indicate a role for IL-38 in the regulation of gd T cell activation through IL1RAPL1, with consequences for auto-inflammatory disease.
Highlights Transfusion of sera of convalescent patients is currently in clinical evaluations to treat COVID-19 patients. The level of neutralizing antibodies vary among convalescent patients and fast and simple methods to identify suitable plasma donations are needed. We compared three methods to determine the SARS-CoV-2 neutralizing activity of human convalescent plasma. An ELISA-based sVNT assay required the lowest biosafety level, was fast and sufficient to identify highly neutralizing plasma samples. Weakly neutralizing samples were more reliable detected by the more challenging lentiviral vector based assays or virus neutralization assays.
Similar to T-helper (Th) cells, CD8+ T cells also differentiate into distinct subpopulations.However, the existence of IL-9-producing CD8 + T (Tc9) cells has not been elucidated so far. We show that murine CD8 + T cells activated in the presence of IL-4 plus TGF-β develop into transient IL-9 producers characterized by specific IFN-γ and IL-10 expression patterns as well as by low cytotoxic function along with diminished expression of the CTL-associated transcription factors T-bet and Eomesodermin. Similarly to the CD4 + counterpart, Tc9 cells required for their differentiation STAT6 and IRF4. Tc9 cells deficient for these master regulators displayed increased levels of Foxp3 that in turn suppressed IL-9 production. In an allergic airway disease model, Tc9 cells promoted the onset of airway inflammation, mediated by subpathogenic numbers of Th2 cells. This support was specific for Tc9 cells because CTLs failed to exert this function. We detected increased Tc9 frequency in the periphery in mice and humans with atopic dermatitis, a Th2-associated skin disease that often precedes asthma. Thus, our data point to the existence of Tc9 cells and to their supportive function in Th2-dependent airway inflammation, suggesting that these cells might be a therapeutic target in allergic disorders.Keywords: Allergic airway inflammation r Atopic dermatitis r CD8 + T cells r IL-9 r Tc9 cells Additional supporting information may be found in the online version of this article at the publisher's web-site 607Introduction IL-9 is a pleiotropic cytokine produced by different cell types such as T cells, innate lymphoid cells, eosinophils, and mast cells [1,2]. IL-9 secretion by T cells was originally linked to Th2-mediated (where Th is T-helper) diseases such as allergic airway inflammation [3,4] and parasite infection [5,6] However, in vitro IL-9 is differently regulated from other classical Th2-cytokines such as IL-4, IL-5, and IL-13. IL-9 is induced by the combination of the Th2-skewing cytokine IL-4 with TGF-β [7] and, under these conditions Th2-cytokines are strongly inhibited [8,9]. Therefore, besides Th1, Th2, Th17, and Treg cells, IL-9-producing cells have been established as an additional Th-cell subset, termed Th9 cells. The differentiation of Th9 cells is governed by the transcription factors IRF4, PU.1, and STAT6 [10,11]. IRF4, also important for Th2-, Th17-, and Tfh-fate decisions [12][13][14][15] regulates IL-9 production directly by binding to the Il9 promoter [10]. Likewise, PU.1 enhances IL-9 production, at least partly by binding to the Il9 promoter [11]. In contrast, STAT6, activated by IL-4, contributes to IL-9 production indirectly. It represses the expression of two transcription factors, Treg-specific Foxp3 and Th1-associated T-bet that inhibit IL-9 production [8,9,16].Similarly to Th cells, CD8 + T cells differentiate into at least four effector subsets with different phenotype: CTLs, Tc2, Tc17, or CD8 + Treg cells [17]. The best characterized CD8 + T-cell subpopulation, CTLs kill infected or tumorogenic cells ...
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