Identification of CD44 as a downstream target of noncanonical NF-κB pathway activated by human T-cell leukemia virus type 1-encoded Tax protein

Our previous study showed Human T-cell leukemia virus type 1 Tax induces osteopontin (OPN) expression by transactivating its promoter. As an extension, we investigated here the possible influence of Tax on CD44, an important receptor for OPN. Co-expression of Tax, but not its NF-κB-defective mutant, significantly increased the reporter gene expression directed by CD44 promoter. Tax-mediated CD44 activation was largely diminished by disrupting an element similar to the noncanonical κβ site found in other IKKα target genes, and further, co-transfection of RelB siRNA abolished CD44 induction by Tax, suggesting an involvement of noncanonical NF-κB pathway in Tax-mediated transactivation. Consistently, chromatin immunoprecipitation revealed a specific interaction of CD44 promoter with RelB-containing complex. Together, these results indicate that D44 gene is one of the downstream target genes of aberrantly activated noncanonical NF-κB signaling by Tax, providing an additional line of evidence explaining how Tax-induced NF-κB signaling is integrated into a fate-determining cellular program.     

Mechanisms of genotype-phenotype correlation in autosomal dominant anhidrotic ectodermal dysplasia with immune deficiency

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RelB regulates Th17 differentiation in a cell-intrinsic manner

The role of the alternative NF-κB pathway is mainly attributed to the lymphoid organ formation and blood cancer. However, its involvement in lymphocyte differentiation is not clearly defined. Recently, we have shown that uncontrolled activation of alternative NF-κB in mice lacking the NF-κB inhibitory protein p100 (p100^?/? mice) hinders plasmablast proliferation and diminishes T cell independent responses. Here we show that hyperactivation of this pathway leads to a cell-intrinsic T cell defects. p100-deficient T helper cells displayed both an activation and a proliferation defect in vitro. In addition, memory T cell formation was impaired in vivo. Moreover, p100^?/? T cells failed to polarize into T helper 17 cells. This phenotype was dependent on increased RelB activation and suboptimal RORγt expression. Thus, our results demonstrate that RelB acts as a negative regulator of T cell activation and Th17 development. Targeting this pathway therefore could be beneficial in Th17-mediated pathologies.