Essential role of NPAT in regulating T cell development and function

Abstract

Abstract The T-cell development process is precisely controlled at different stages. For example, cell proliferation during T cell development is limited to immature double negative (DN) thymocytes. Here we want to investigate the mechanism of stage-specific regulation of cell proliferation in this process. Nuclear protein ataxia-telangiectasia (NPAT) is an in vivo substrate of cyclin E-Cdk2 kinase and plays a critical role in coordinating histone gene expression during the G1/S-phase transition and to ensure S-phase entry, thus play a regulatory role in determining the proliferation level of different cells. By the using of conditional gene deletion in thymocytes, we found that ablation of NPAT resulted in severe thymocyte development defect including reduced thymocyte number and developmental arrest from ISP to DP, indicating a critical role of NPAT in thymocyte development. We have also constructed a mouse strain that ablates NPAT expression in peripheral mature T cells. NPAT deficiency in peripheral T cells only resulted in a mild decrease in the number of CD4 and CD8 cells, while maintained normal T-cell homeostasis in peripheral lymphoid organs. However, the proliferative capacity of naïve CD4 or CD8 T cells in NPAT cKO mice were impaired upon activation, which correlated with less severe symptoms in experimental autoimmune encephalomyelitis (EAE) disease upon antigen-immunization. We are currently exploring the regulation mechanism of NPAT function in different cell stages and will test the possibility of targeting NPAT in treat autoimmune diseases.