The NF-{u0199}B transcription factor, c-Rel, is involved in IL-21 gene expression and development of T helper cell subsets

Abstract

CD4{u207A} T lymphocytes play an important role in the adaptive immune response that protects the host from a broad range of pathogenic microorganisms. They have the ability to differentiate into different subsets depending on the micro-environment through the actions of specific transcription factors. The work described in this thesis demonstrates that c-Rel, one of the NF-{u0199}B transcription factor family members, is required for IL-21 gene expression in CD4{u207A} T cells and also for development of IL-21 associated Th subsets. Firstly, c-Rel is involved in the regulation of IL-21 gene expression and T(FH) development. IL-21 messenger RNA and protein levels were reduced in the CD4{u207A} cells of c-Rel knock-out (rel{u207B}/{u207B}) mice when compared to wild-type (rel{u207A}/{u207A}) mice in both in vitro and in vivo models. A binding site identified in the proximal promoter of il21 was confirmed to bind c-Rel in vitro and in vivo, and to regulate the gene expression of IL-21 in T cells. The development of IL-21-dependent T(FH) and germinal centre B cell was also impaired in rel{u207B}/{u207B} mice. The administration of IL-21 protein to rel{u207B}/{u207B} mice rescued the development of TFH cells, but not germinal centre B cells. Secondly, c-ReI regulates the development of Th17 cells in experimental autoimmune encephalomyelitis (EAE). rel{u207B}/{u207B} mice were confirmed to be resistant to EAE, and were demonstrated a cell intrinsic Th17 deficiency using mixed chimera and adoptive transfer EAE experiments. c-Rel was found to act in the T cell receptor signaling pathway in the early stage of Th17 development, and to bind to the promoter of the master transcription factor of Th17 development, ROR{u03B3}t and control its expression. c-ReI was also revealed to be present in the signalling pathway of CD28 co-stimulation that causes Th17 repression. Thirdly, the number of regulatory T cells (Treg) was confirmed to be significantly reduced in rel{u207B}/{u207B} EAE mice and adoptive transfer experiments suggest that EAE development is not only associated with Th17 cell infiltration but is also dependent on the equilibrium between Th17 and Treg cells. Taken together, c-Rel plays an important role in the development of CD4{u207A} T cell subsets. It affects TFH and Th17 cell development by regulating the expression of IL-21 and ROR{u03B3}t respectively. These findings point to a novel and critical role for c-Rel in the control of CD4{u207A} T cell development and in activated T cell-dependent autoimmune responses and inflammation, and offer new potential therapeutic targets in associated autoimmune inflammatory diseases.