Dedicator of cytokinesis 8 (DOCK8) mutation impairs the differentiation of helper T cells by regulating the glycolytic pathway of CD4 T cells.

Dedicator of cytokinesis 8 (DOCK8) deficiency is a primary immunodeficiency disease caused by mutations in exon 45 of the gene. The clinical signs primarily consist of increased serum IgE levels, eczema, repeated skin infections, allergies, and upper respiratory tract infections. Using CRISPR/Cas9 technology, we generated a exon 45 mutation in mice, mirroring the mutation found in patients. The results indicated that mutation impairs peripheral T cell homeostasis, disrupts regulatory T cells (Tregs) development, increases ICOS expression in Tregs within peripheral lymph nodes (pLn), and promotes Th17 cell differentiation within the spleen and pLn. Upon virus infection, mutation CD4 T cells have a Th2 effector fate. RNA-bulk sequencing data revealed alternations in the mTOR pathway of mutant CD4 T cells. We observed that mutation upregulates the glycolysis levels in CD4 T cells, which is related to the Akt/mTOR/S6/HIF-1α pathway. In summary, our research elucidates that DOCK8 regulates the differentiation of helper T cells by modulating the glycolytic pathway in CD4 T cells, thereby advancing the comprehension and offering potential treatment of diseases in DOCK8-deficient patients.