mRNA-seq of naïve CD4+ T cells from uninfected or schistosome-infected mice

Severe infection commonly results in T cell aging, which leads to impaired pathogen clearance or increased secondary infection in both humans and animals. However, the exact mechanisms remain poorly understood. Here, we demonstrated that severe infection-induced IL-33 production resulted in acute thymic involution-mediated naive T cell aging and impaired host control of infection in mouse disease models of schistosomiasis or sepsis. Furthermore, we illustrated that IL-33 triggered excessive generation of medullary thymic epithelial cell (mTEC) IV (thymic tuft cells) in a Pou2f3-dependent manner, as a consequence, disturbed mTEC/cortical TEC (cTEC) compartment and caused acute thymic involution during severe infection. More importantly, IL-33 deficiency or IL-33 receptor ST2 deficient thymus transplantation rescued T-cell immunity to better control infection in mice. Our findings not only uncover a novel link between severe infection-induced IL-33 and thymic involution-mediated naive T cell aging, but also suggest that targeting IL-33 or ST2 is a promising strategy to rejuvenate T cell immunity to better control severe infection. mRNA sequence of naïve CD4+T cells from uninfected or schistosome-infected mice