Abstract
During T-cell-mediated inflammatory responses, T cells are activated upon recognizing specific antigens presented by antigen-presenting cells. This recognition initiates signaling through the TCR and CD28, leading to their activation and subsequent clonal expansion. Within the signaling cascades triggered by TCR and CD28 engagement, the CD28-PI3K pathway serves as a central regulator of metabolic reprogramming in T cells, supporting the biosynthetic needs essential for their effective proliferation. In this study, we found that the regulation of PANK4 plays a role in TCR/CD28-mediated CD4(+) T-cell proliferation by regulating de novo lipid synthesis. The CD28 signaling pathway negatively regulates PANK4 through direct binding with PDK1, thereby controlling de novo lipid synthesis for CD4(+) T-cell proliferation. Interestingly, we found that Pank4-deficient CD4(+) T cells enhance coenzyme A synthesis and glutaminolysis, whereby glutamine contributes carbon for fatty acid synthesis and provides nitrogen for coenzyme A biosynthesis. The regulatory role of PANK4 in CD4(+) T-cell proliferation was confirmed in models of experimental colitis and influenza A virus infection, where Pank4-deficient CD4(+) T cells exhibited greater expansion than their wild-type counterparts when co-transferred. Our findings suggest that PANK4 regulation of de novo lipid synthesis is crucial for TCR/CD28-induced CD4(+) T-cell proliferation and represents a potential target for modulating general CD4(+) T-cell responses.