mTOR inhibition alleviates CD8+ T-cell senescence in activated phosphoinositide 3-kinase δ syndrome 2 patients

Background We investigated the clinical and immunological features in a Chinese cohort of activated phosphatidylinositol 3-kinase δ syndrome 2 (APDS2) and assessed the efficacy of Rapamycin therapy and the underlying mechanism.Results The shared clinical manifestation of patients included recurrent respiratory tract infection, lymphadenopathy, persistent or recurrent splenomegaly, and hepatomegaly. Three patients carry PIK3R1 c.1425 + 1G > A mutation, and one patient has the mutation c.1425 + 2T > G. Patients have defective humoral immunity with decreased B lymphocytes, especially memory B cells, and suffered from decreased naïve T cells and elevated senescent CD8+ T cells. Two patients after rapamycin therapy showed improved clinical symptoms. They also have decreased CD8+ effector memory T cells and terminal effector memory cytotoxic T cells. TCF1 was downregulated in CD8+ T cells of PIK3R1 patients but upregulated after Rapamycin treatment, which was correlated with decreased senescent CD8+ T cells.Conclusions mTOR inhibitor rapamycin improved clinical symptoms in APDS2 patients and reversed CD8+ T cell senescence through TCF1-dependent signal pathway.