Integrated STAT3 and Ikaros Zinc Finger Transcription Factor Activities Regulate Bcl-6 Expression in CD4+ Th Cells

Abstract

Bcl-6 (B cell lymphoma-6) is a transcriptional repressor required for the differentiation of T follicular helper (TFH) cell populations. Currently, the molecular mechanisms underlying the transcriptional regulation of Bcl-6 expression are unclear. Here, we have identified the Ikaros zinc finger (IkZF) transcription factors Aiolos and Ikaros as novel regulators of Bcl-6. We found that increased expression of Bcl-6 in CD4+ T helper cell populations correlated with enhanced enrichment of Aiolos and Ikaros at the Bcl6 promoter. Furthermore, overexpression of Aiolos or Ikaros, but not the related family member Eos, was sufficient to induce Bcl6 promoter activity. Intriguingly, STAT3, a known Bcl-6 transcriptional regulator, physically interacted with Aiolos to form a transcription factor complex capable of inducing the expression of Bcl6 and the TFH-associated cytokine receptor Il6ra. Importantly, in vivo studies revealed that the expression of Aiolos was elevated in antigen-specific TFH cells compared to that observed in non-TFH effector T helper cells generated in response to influenza infection. Collectively, these data describe a novel regulatory mechanism wherein STAT3 and the IkZF transcription factors Aiolos and Ikaros cooperate to regulate Bcl-6 expression.

Inhibition of glucose metabolism selectively targets autoreactive follicular helper T cells

“…1g ): TC CD4 + T cells inside GCs showed abundant mTOR staining as compared to B6 CD4 + T cells, which expressed mTOR in the T cell zone. STAT3 activation induces Bcl6 expression and STAT3 deficiency impaired T FH cell differentiation 28 – 30 . However, IL-21-mediated STAT3 phosphorylation was significantly decreased in CD4 + T cells from SLE patients 31 .…”

Insights Into the Molecular Mechanisms of T Follicular Helper-Mediated Immunity and Pathology

“…IL-6–STAT3 and IL-21–STAT3 signaling can promote Tfh cell differentiation by inducing Bcl6 expression ( 6 , 7 , 146 , 147 ). STAT3 cooperates with the Ikaros zinc finger TFs, Aiolos, and Ikaros, to regulate Bcl6 expression ( 148 ). IL-6-mediated STAT3 activation restricts IL-2Rα expression to limit Th1 cell differentiation ( 107 ).…”

Correlates of Follicular Helper Bias in the CD4 T Cell Response to a Retroviral Antigen

“…Acute viral infections typically induce a CD4 + T cell response that is almost exclusively composed of Tfh and Th1 cells, in approximately equal proportion. Indeed, the ratio of Tfh to Th1 cells in the CD4 + T cell response to acute lymphocytic choriomeningitis virus (LCMV) has been amply reported close to 1 and 2 for LCMV Armstrong ( 9 – 14 ) and clone 13 (Cl13) ( 15 – 19 ), respectively, and similar results were also reported for influenza A virus infection ( 20 – 23 ).…”

“…Thus, FV infection induces primarily a Tfh phenotype in env-reactive EF4.1 CD4 + T cells and, to a much lesser extent, a Th1 phenotype (Figure 1 E), whereas Th2, Th17, Treg, or CTL differentiation is not typically observed ( 37 , 39 , 42 ). This skewing in favor of Tfh differentiation was much more pronounced in FV infection, where there are on average 5.2 times more Tfh than Th1 cells, than in other acute viral infections, where this ratio is consistently reported to be closer to 1 ( 9 – 23 ) (Figure 1 F).…”