CARD11-dependent signaling in T cells is critical for the activation of multiple AP-1 transcription factor complexes.

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Presentation Time: 11:30 AM - 12:45 PM
Poster Board Number: B721
Abstract ID: 5984

Presenting Author:
Bradly M. Bauman , Postdoctoral Associate at Uniformed Services Univ. of the Hlth. Sci., Henry M. Jackson Foundation for the Advancement of Military Medicine

Abstract:

The CARD11 scaffold enables TCR-induced NF-κB, mTORC1 and JNK signaling. While the requirement of CARD11 for NF-κB stimulation is well known, it remains unclear if/how CARD11 influences other transcription factors (TFs) essential for T cell activation: AP-1 and NFAT. We sought to delineate the importance of CARD11 in activating AP-1- or NFATc1-dependent transcription in human T cells, employing mitogen-activated wild-type (WT) or CARD11 KO Jurkat T cells. RNA-seq analysis revealed significant downregulation of AP-1-mediated transcriptional programs in CARD11 KO cells, with a concomitant increase in NFATc1 expression. Although JNK inhibition in WT cells had a surprisingly minimal impact on AP-1 activation, loss of CARD11 substantially reduced mitogen-induced AP-1 component expression and activity, encompassing all canonical JUN and FOS family members. We further demonstrated that deleterious CARD11 variants derived from CARD11-associated Atopy with Dominant Interference of NF-κB Signaling (CADINS) disease patients also impaired AP-1 function. Conversely, JNK inhibition in WT T cells enhanced NFATc1 activity with concomitant upregulation of the NFAT-dependent T_H2 master regulator GATA3, congruent with enhanced GATA3 induction in CADINS patient T cells. Our novel findings indicate that CARD11 governs the activation of AP-1 and NFAT TF complexes originally thought to be induced via CARD11-independent pathways, with implications for human T cell differentiation and function.