Histone methyltransferase Nsd2 is required for follicular helper T cell differentiation

Abstract

Follicular helper T (Tfh) cells provide essential help for humoral immune response. Transcriptional factor Bcl6 is the master regulator for Tfh generation and is induced very early after T cell activation in a CD28-dependent manner, but how CD28 signal promotes Bcl6 early expression remains unknown. Here we found that CD28 signal quickly induces expression of the H3K36me2 methytransferase Nsd2, which is required for Bcl6 expression as early as the first cell division after T cell activation. Nsd2 deficiency in T cells leads to decreased Bcl6 expression, impaired Tfh generation, compromised germinal center response, and delayed virus clearance. Ectopic Bcl6 expression rescues the Tfh defect of Nsd2 KO cells. ICOS signal is dispensable for early Nsd2 induction but required for sustained Nsd2 expression, which is critical for Tfh maintenance. Overexpression of Nsd2 increases Bcl6 expression and enhances Tfh generation; 4-mo-old mice even develop spontaneous Tfh. Overall, our study reveals Nsd2 as a critical epigenetic regulator for Tfh differentiation.

Mechanism of Follicular Helper T Cell Differentiation Regulated by Transcription Factors

“…Bcl6 expression is induced by IL-6-STAT1/STAT3 signaling [43], and it is driven very early after T cell activation in a CD28-dependent manner [44]. The E3 ubiquitin ligase Itch is essential for Bcl6 expression at the early stage of Tfh cell development [45].…”

Role of Epigenetics in the Regulation of Immune Functions of the Skin

“…Deubiquitination of histones and DNA methylation in T cells can promote their expansion (Dufner et al, 2015;Lee et al, 2001;Manna et al, 2015). Histone acetylation and methylation have also been reported to positively regulate T-cell development (Boucheron et al, 2014;Gao et al, 2017;Gö schl et al, 2018;Long et al, 2020;Philips et al, 2016;Takikita et al, 2016;Toubai et al, 2018). T helper type 1 (Th1) cells are positively driven by citrullination (Liu et al, 2018b) and negatively regulated by DNA demethylation (Carty et al, 2018).…”

“…Histone demethylase KDM6A has shown activity in urothelium (Kobatake et al, 2020), histone methyltransferase G9a in KCs (Li et al, 2018), and SETDB1 in intestinal epithelial cells (Ju zni c et al, 2020). Inflammatory cytokines have been also shown to be positively regulated by HDAC3 in intestinal epithelial cells (Navabi et al, 2017), HDAC5 in bronchial epithelial cells (Luo et al, 2019), and HDAC6 in bronchial epithelial cells (Lin et al, 2020). Histone demethylation enzymes JMJD3 and SET7/9 positively regulate the production of antimicrobial peptides by KCs (Gschwandtner et al, 2014) and inflammatory cytokines by bronchial epithelial cells (He et al, 2015), respectively.…”

“…DNA demethylation: TET1(Ryu et al, 2019), TET2(Liu et al, 2020) Histone deacetylation: HDAC3(Navabi et al, 2017), HDAC5(Luo et al, 2019), HDAC6(Lin et al, 2020), SIRT1(Minagawa et al, 2015) …”

The direct and indirect regulation of follicular T helper cell differentiation in inflammation and cancer

“…Recent research has shown that deficiency of the H3K36me2 methyltransferase Nsd2 in T cells leads to decreased Bcl‐6 expression and impaired Tfh cell generation. CD28 activation quickly induces the expression of Nsd2 (Long et al, 2020). In addition, the transcription factors BATF (basic leucine zipper ATF‐like transcription factor), IRF4 (interferon regulatory factor 4), TCF‐1, LEF‐1 (lymphoid enhancer‐binding factor 1), and Thpok (T‐helper‐inducing POZ/Krueppel‐like factor) play essential roles in the regulation of Bcl‐6 (Y. S. Choi et al, 2015; Vacchio et al, 2019; Vinuesa et al, 2016).…”