Dominant interfering CARD11 variants disrupt JNK signaling in T cells

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Abstract Previous studies in mice implicated c-Jun N-terminal kinase 1 and 2 (JNK1/2) as important determinants of helper CD4+ T cell differentiation through their influence on AP-1 and NF-AT-dependent gene transcription. However, mechanisms governing the JNK signaling pathway in human lymphocytes remain nebulous. CARD11 is a critical scaffold protein in T and B cells that connects antigen receptor (AgR) engagement to downstream transcriptional programs responsible for effector cell survival, proliferation and differentiation. Although CARD11 is best known for facilitating AgR-induced NF-κB activation, a handful of studies have shown it is also required for AgR-induced mTORC1 and JNK2 signaling. Using both CARD11-deficient Jurkat T cells and primary human T cells, we found that phosphorylation of both JNK1 and JNK2 in response to T cell receptor (TCR)/CD28 activation is dependent on CARD11. Furthermore, we demonstrate that heterozygous dominant negative (DN) CARD11 mutations derived from patients with CARD11-associated atopy with dominant interference of NF-κB signaling (CADINS) disease also disrupt TCR-dependent JNK1/2 phosphorylation and c-Jun accumulation with variable potency, closely mirroring the extent of impaired NF-κB activation. Considering that loss of either JNK1 or JNK2 in mice contributes to reduced IFN-γ production and skewed Th2 phenotypes, our findings suggest that defective JNK signaling in CD4+ T cells may contribute to severe atopic disease manifestations noted in most CADINS patients. Ongoing studies will define differences in specific JNK-dependent gene signatures that correlate with specific CARD11 DN variants and clinical phenotypes.