Octamer-dependent transcription in T cells is mediated by NFAT and NF-κB

Abstract

The transcriptional co-activator BOB.1/OBF.1 was originally identified in B cells and is constitutively expressed throughout B cell development. BOB.1/OBF.1 associates with the transcription factors Oct1 and Oct2, thereby enhancing octamer-dependent transcription. In contrast, in T cells, BOB.1/OBF.1 expression is inducible by treatment of cells with PMA/Ionomycin or by antigen receptor engagement, indicating a marked difference in the regulation of BOB.1/OBF.1 expression in B versus T cells. The molecular mechanisms underlying the differential expression of BOB.1/OBF.1 in T and B cells remain largely unknown. Therefore, the present study focuses on mechanisms controlling the transcriptional regulation of BOB.1/OBF.1 and Oct2 in T cells. We show that both calcineurin- and NF-κB-inhibitors efficiently attenuate the expression of BOB.1/OBF.1 and Oct2 in T cells. In silico analyses of the BOB.1/OBF.1 promoter revealed the presence of previously unappreciated combined NFAT/NF-κB sites. An array of genetic and biochemical analyses illustrates the involvement of the Ca2+/calmodulin-dependent phosphatase calcineurin as well as NFAT and NF-κB transcription factors in the transcriptional regulation of octamer-dependent transcription in T cells. Conclusively, impaired expression of BOB.1/OBF.1 and Oct2 and therefore a hampered octamer-dependent transcription may participate in T cell-mediated immunodeficiency caused by the deletion of NFAT or NF-κB transcription factors.

The transcriptional coactivator Bob1 promotes the development of follicular T helper cells via Bcl6

“…In CD4 + T cells, Bob1 directly contributes to the Ifng and Il2 promoter activities and indirectly affects Th2 cytokine expression, thereby shaping the balance between Th1 and Th2 immunity (Brunner et al , 2007). More recently, we demonstrated that—similar to B cells (Kilzheimer et al , 2015)—NFAT and NF‐κB signaling pathways are important for Bob1 expression in T cells (Mueller et al , 2013). Interestingly, NFAT—and especially NFATc1—is a dominant transcription factor in follicular T cells (Vaeth et al , 2014) and likely accounts for Bob1 expression in these cells.…”

Store-Operated Ca 2+ Entry in Follicular T Cells Controls Humoral Immune Responses and Autoimmunity

“…Accordingly, NFAT2αA expression in Stim1Stim2 -deficient Tfh cells was markedly reduced (Figure 6B), whereas that of NFAT2β (driven by the Nfat2 P2 promoter) and NFAT1 was normal (Figure S6A). Further analysis of Stim1Stim2 -deficient Tfh cells showed that expression of numerous NFAT-dependent molecules including CD40L, PD-1, ICOS, CXCR5, IL-21 and IL-4 (Figures 5 and S5H-L) (Muller and Rao, 2010; Oestreich et al, 2008; Vaeth et al, 2014) and transcription factors including EGR2, BOB1 (encoded by Pou2af1 ), and HIF1α (Mueller et al, 2013; Muller and Rao, 2010) that contribute to Tfh differentiation was decreased (Figure S6B). These findings suggest that SOCE regulates the differentiation of Tfh cells by controlling the expression of NFAT2αA, which may represent an early checkpoint for Tfh cell fate determination.…”

POU2AF1 Functions in the Human Airway Epithelium To Regulate Expression of Host Defense Genes

“…Consistent with the in vitro finding, smoking caused significantly down-regulated POU2AF1 expression in our initial cohort (−1.7 fold, p<10 −4 , Figure 4C). The down-regulation of POU2AF1 was unexpected as two known smoking-heightened pathways, NF-Kappa B and the endoplasmic reticulum stress (ER stress) are positive regulators of POU2AF1 expression in lymphocytes 24,25 . To verify these results, we assessed POU2AF1 expression in an independent microarray cohort of small airway epithelium 26 , observing a 1.9-fold down-regulation of POU2AF1 in smokers (Figure 4D).…”

“…It is constitutively expressed in B cells, and is inducible in T cells upon stimulation 4 . The stimuli that can up-regulate POU2AF1 include IL4, LPS, CD40 and BCR signaling 17 and phorbol myristate acetate plus ionomycin 24 . Sporadic literature, however, suggests POU2AF1 might have a role in cells other than lymphocytes.…”