GSE131965
Protein Kinase 2 (CK2) Controls CD4+ T-cell Effector Function in the Pathogenesis of Colitis
Crohn's disease (CD) is one of the major forms of inflammatory bowel disease (IBD), characterized by chronic inflammation of the gastrointestinal tract. CD is associated with aberrant Th1 and Th17 responses accompanied by high levels of IFN-g and IL-17, respectively. Protein kinase 2 (CK2) is a highly conserved serine-threonine kinase that is involved in several signal transduction pathways which regulate inflammatory responses. CK2 promotes Th17 cell differentiation and suppresses the generation of Foxp3+ regulatory T cells. The function of CK2 in CD4+ T-cells during the pathogenesis of CD is unknown. We utilized T-cell induced colitis model, transferring CD45RBhi naïve CD4+ T-cells from CK2afl/fl littermate control and CK2afl/fldLck-Cre mice into Rag1-/- mice. We demonstrate that CD4+ T-cells from CK2afl/fldLck-Cre mice fail to induce wasting disease and significant intestinal inflammation, which is associated with decreased IL-17A+, IFN-g+ and double positive IL-17A+ IFN-g+ CD4+ T-cells in the spleen and colon. Further, we determine that CK2a regulates CD4+ T-cell proliferation through a cell-intrinsic manner. CK2a is also important in controlling CD4+ T-cell responses by regulating NFAT2, which is vital for T-cell activation and proliferation. Thus, our data demonstrate that CK2a contributes to the pathogenesis of colitis by promoting CD4+ T-cell proliferation and Th1 and Th17 responses, and that targeting CK2 kinase activity may be a novel therapeutic treatment for CD patients. Overall design: Colonic CD45+CD3+CD4+ T-cells were sorted from recipient Rag1-/- mice at 6 weeks after transfer. Total RNA was extracted from FACS-sorted CD4+ T-cells using the miRNeasy Mini Kit (Qiagen, Venlo, Netherlands) according to the manufacturer's protocols and submitted to GENEWIZ (South Plainfield, NJ) for RNA sequencing (RNA-seq) and bioinformatics analysis.