Protein kinase CK2 is a serine/threonine kinase composed of two catalytic subunits (CK2α and/or CK2α′) and two regulatory subunits (CK2β). CK2 promotes cancer progression by activating the NF-κB, PI3K/AKT/mTOR, and JAK/STAT pathways, and also is critical for immune cell development and function. The potential involvement of CK2 in CD8+ T cell function has not been explored. We demonstrate that CK2 protein levels and kinase activity are enhanced upon mouse CD8+ T cell activation. CK2α deficiency results in impaired CD8+ T cell activation and proliferation upon TCR stimulation. Furthermore, CK2α is involved in CD8+ T cell metabolic reprogramming through regulating the AKT/mTOR pathway. Lastly, using a mouse Listeria monocytogenes infection model, we demonstrate that CK2α is required for CD8+ T cell expansion, maintenance, and effector function in both primary and memory immune responses. Collectively, our study implicates CK2α as an important regulator of mouse CD8+ T cell activation, metabolic reprogramming, and differentiation both in vitro and in vivo.
IntroductionMyeloid cells play a critical role in the pathogenesis of Inflammatory Bowel Diseases (IBDs), including Ulcerative Colitis (UC) and Crohn’s Disease (CD). Dysregulation of the JAK/STAT pathway is associated with many pathological conditions, including IBD. Suppressors Of Cytokine Signaling (SOCS) are a family of proteins that negatively regulate the JAK/STAT pathway. Our previous studies identified that mice lacking Socs3 in myeloid cells developed a hyper-activated phenotype of macrophages and neutrophils in a pre-clinical model of Multiple Sclerosis.MethodsTo better understand the function of myeloid cell Socs3 in the pathogenesis of colitis, mice with Socs3 deletion in myeloid cells (Socs3ΔLysM) were utilized in a DSS-induced colitis model.ResultsOur results indicate that Socs3 deficiency in myeloid cells leads to more severe colitis induced by DSS, which correlates with increased infiltration of monocytes and neutrophils in the colon and increased numbers of monocytes and neutrophils in the spleen. Furthermore, our results demonstrate that the expression of genes related to the pathogenesis and diagnosis of colitis such as Il1β, Lcn2, S100a8 and S100a9 were specifically enhanced in Socs3-deficient neutrophils localized to the colon and spleen. Conversely, there were no observable differences in gene expression in Ly6C+ monocytes. Depletion of neutrophils using a neutralizing antibody to Ly6G significantly improved the disease severity of DSS-induced colitis in Socs3-deficient mice.DiscussionThus, our results suggest that deficiency of Socs3 in myeloid cells exacerbates DSS-induced colitis and that Socs3 prevents overt activation of the immune system in IBD. This study may provide novel therapeutic strategies to IBD patients with hyperactivated neutrophils.
Multiple sclerosis (MS) is associated with a dysregulated JAK/STAT signaling pathway. Suppressors of cytokine signaling (SOCS) negatively regulate the JAK/STAT pathway. MS patients with disease affecting the cerebellum display rapid progression and poor prognosis. Previous data from our laboratory demonstrates a severe, brain-targeted form of experimental autoimmune encephalomyelitis (EAE) in mice lacking Socs3 in myeloid cells (Socs3ΔLysM), with increased cerebellar infiltration of primed neutrophils. Here, we induced EAE in mice lacking Socs3 specifically in neutrophils (Socs3ΔLy6G; n=26) and Ly6G−/+ control mice (n=13), and examined disease progression, neutrophil populations and CD4+ T-cell polarization at disease peak. Ly6G−/+ mice exhibited clinical signs of classical EAE, whereas Socs3ΔLy6G mice exhibited clinical signs of brain-targeted EAE, similar to Socs3ΔLysM mice. An analysis of the cerebellar cell infiltrate in Socs3ΔLy6G mice demonstrated an increased cellularity (p=0.005), which was comprised of both an increase in the percentage (p=0.020) and total number (p<0.001) of cerebellar neutrophils. Neutrophils from Socs3ΔLy6G mice exhibited a primed phenotype with increased surface expression of CD11b (p=0.084) and reduced expression of CD62L (p<0.001). Additionally, Socs3ΔLy6G mice exhibited an increase in the percent of cerebellar CD4+ T-cells (p=0.018) and a shift toward IFN-γ-producing Th1 CD4+ T-cells (p=0.012). These data conclusively document that neutrophil-specific deficiency of Socs3 is sufficient to induce brain-targeted EAE. Future studies will identify targets to dampen the role of neutrophils in brain-targeted autoimmune neuroinflammation.
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