Role of NF-kappaB c-Rel O-GlcNAcylation in the regulation of cytotoxic T cell function

Abstract

Abstract Autoimmunity in type 1 diabetes (T1D) is primarily caused by destruction of insulin producing pancreatic beta cells by cytotoxic T cells, resulting in hyperglycemia. Adverse pathological effects of hyperglycemia include the increased O-GlcNAcylation of cellular proteins. We found that the transcription factor nuclear factor kappaB (NF-kB) subunit c-Rel is a target of O-GlcNAcylation at serine residue 350 in T cells. c-Rel is the major regulator of CD4 and CD8 T cell function and T regulatory cell development that controls autoimmunity and immunosuppression, respectively. c-Rel O GlcNAcylation increases the expression of pro-autoimmune cytokines and decreases the expression of the transcription factor forkhead box P3 (FOXP3) in CD4 T cells. However, the role of c-Rel O-GlcNAcylation in cytotoxic T cells remains unknown. The cell death pathways mediated by Fas ligand (FasL) and TNF-related apoptosis-inducing ligand (TRAIL) are major contributors of T cell mediated cytotoxicity. Our preliminary microarray study showed that FasL and TRAIL expressions are dependent on O-GlcNAcylated c-Rel. We also found that hyperglycemia and c-Rel O-GlcNAcylation enhances FasL expression in both CD4 and CD8 T cells. Mechanistically, O-GlcNAcylation enhances and a point mutation at S350 O-GlcNAcylation site prevents c-Rel binding to FasL promoter. Our future studies aim at studying how hyperglycemia-induced c-Rel O-GlcNAcylation enhances cytotoxic ligand expressions in T cells, augmenting their potential to destruct host cells in T1D. This study will define the critical role of c-Rel O-GlcNAcylation in cytotoxic T cell function, revealing a new molecular mechanism that could be targeted to control autoreactive T cell function in T1D. P.R was supported by National Institute of Allergy and Infectious Diseases at National Institute of Health grants R01 AI116730 and R21 AI144264, and National Cancer Institute at National Institute of Health grant R21 CA246194. JTC was supported by National Institute of Health NIH/NEI T32 pre-doctoral training grant T32EY007157.