IL-1 receptor 1 signaling shapes the development of viral antigen-specific fi c CD4+

초록

Background The innate immune cytokine interleukin (IL)-1 can affect T cell immunity, a critical factor in host defense. In a previous study, we identified fi ed a subset of human CD4+ + T cells which express IL-1 receptor 1 (IL-1R1). However, the expression of such receptor by viral antigen-specific fi c CD4+ + T cells and its biological implication remain largely unexplored. This led us to investigate the implication of IL-1R1 in the development of viral antigen-specific fi c CD4+ + T cell responses in humans, including healthy individuals and patients with primary antibody deficiency fi ciency (PAD), and animals. Methods We characterized CD4+ + T cells specific fi c for SARS-CoV-2 spike (S) protein, influenza fl uenza virus, and cytomegalovirus utilizing multiplexed single cell RNA-seq, mass cytometry and fl ow cytometry followed by an animal study. Findings In healthy individuals, CD4+ + T cells specific fi c for viral antigens, including S protein, highly expressed IL-1R1. IL-1 beta beta promoted interferon (IFN)-gamma gamma expression by S protein-stimulated CD4+ + T cells, supporting the functional implication of IL-1R1. Following the 2nd dose of COVID-19 mRNA vaccines, S protein-specific fi c CD4+ + T cells with high levels of IL-1R1 increased, likely reflecting fl ecting repetitive antigenic stimulation. The expression levels of IL-1R1 by such cells correlated with the development of serum anti-S protein IgG antibody. A similar fi nding of increased expression of IL-1R1 by S protein-specific fi c CD4+ + T cells was also observed in patients with PAD following COVID-19 mRNA vaccination although the expression levels of IL-1R1 by such cells did not correlate with the levels of serum anti-S protein IgG antibody. In mice immunized with COVID-19 mRNA vaccine, neutralizing IL-1R1 decreased IFN-gamma gamma expression by S protein-specific fi c CD4+ + T cells and the development of anti-S protein IgG antibody. Interpretation Our results demonstrate the significance fi cance of IL-1R1 expression in CD4+ + T cells for the development of viral antigen-specific fi c CD4+ + T cell responses, contributing to humoral immunity. This provides an insight into the regulation of adaptive immune responses to viruses via the IL-1 and IL-1R1 interface. Funding Moderna to HJP, National Institutes of Health (NIH) 1R01AG056728 and R01AG055362 to IK and KL2 TR001862 to JJS, Quest Diagnostics to IK and RB, and the Mathers Foundation to RB.

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