Hyperactive PI3Kδ predisposes naive T cells to activation via aerobic glycolysis programs

Activated phosphoinositide 3-kinaseδsyndrome(APDS)is an autosomal-dominant combined immunodeficiency disorder resulting from pathogenic gain-of-function(GOF)mutations in the PIK3CD gene.Patients with APDS display abnormal T cell homeostasis.However,the mechanisms by which PIK3CD GOF contributes to this feature remain unknown.Here,with a cohort of children with PIK3CD GOF mutations from multiple regions of China and a corresponding CRISPR/Cas9 gene-edited mouse model,we reported that hyperactive PI3Kδdisrupted TNaive cell homeostasis in the periphery by intrinsically promoting the growth,proliferation,and activation of TNaive cells.Our results showed that PIK3CD GOF resulted in loss of the quiescence-associated gene expression profile in naive T cells and promoted naive T cells to overgrow,hyperproliferate and acquire an activated functional status.Naive PIK3CD GOF T cells exhibited an enhanced glycolytic capacity and reduced mitochondrial respiration in the resting or activated state.Blocking glycolysis abrogated the abnormal splenic T cell pool and reversed the overactivated phenotype induced by PIK3CD GOF in vivo and in vitro.These results suggest that enhanced aerobic glycolysis is required for PIK3CD GOF-induced overactivation of naive T cells and provide a potential therapeutic approach for targeting glycolysis to treat patients with APDS as well as other immune disorders.

Phenotypic characterization of patients with activated PI3Kδ syndrome 1 presenting with features of systemic lupus erythematosus

Activated phosphoinositide 3-kinase d syndrome 1(APDS1)is a primary immunode-ficiency disease caused by gain-of-function mutations in PIK3CD.Clinical features of autoimmune disease have been reported in patients with APDS1.In this study,we reported three patients with APDS1 presenting with systemic lupus erythematosus(SLE)phenotype.The clinical manifestations included recurrent respiratory tract infection,lymphoproliferation,Coombs-positive hemolytic anemia,decreased complement fractions,positive antinuclear antibodies,renal complications related to SLE associated diseases,which met the clinical spectrum of APDS1 and the classification criteria of SLE.The immunological phenotype included an inversion in the CD4:CD8 ratio,an increase in both non-circulating Tfh CD4^(+)memory T and circulating Tfh populations,a low level of recent thymic emigrant T cells,overexpression of CD57 on T cells,and a decrease in B cells with fewer antibody class switch recombination.These phenotypes detected in patients with APDS1 presenting with SLE were resemble that in patients with APDS1 presenting without SLE.Meanwhile,we described the effect of glucocorticoids and rapamycin therapy on patients with APDS1.The phosphorylation of S6 at Ser235/236 was inhibited in patients with APDS1 who underwent glucocorticoids therapy,including two who presented with SLE phenotype.The phosphorylation of AKT at Ser473 and phosphorylation of S6 at Ser235/236 were inhibited in other patients with APDS1 who underwent rapamycin therapy.Here,we showed the coexistence of immunodeficiency and SLE phenotype in APDS1,and the inhibition of rapamycin in activated Akt-mTOR signaling pathway.