The transcriptional repressor Bcl-6 is linked to the development of both CD4+ T follicular helper (TFH) and central memory T (TCM) cells. Here, we demonstrate that in response to decreased IL-2 signalling, T helper 1 (TH1) cells upregulate Bcl-6 and co-initiate TFH- and TCM-like gene programs, including expression of the cytokine receptors IL-6Rα and IL-7R. Exposure of this potentially bi-potent cell population to IL-6 favours the TFH gene program, whereas IL-7 signalling represses TFH-associated genes including Bcl6 and Cxcr5, but not the TCM-related genes Klf2 and Sell. Mechanistically, IL-7-dependent activation of STAT5 contributes to Bcl-6 repression. Importantly, antigen-specific IL-6Rα+IL-7R+ CD4+ T cells emerge from the effector population at late time points post influenza infection. These data support a novel role for IL-7 in the repression of the TFH gene program and evoke a divergent regulatory mechanism by which post-effector TH1 cells may contribute to long-term cell-mediated and humoral immunity.

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.

Scope The long-term effect of exposure to relevant dietary levels of genistein (GEN) on estrogen receptor-positive (ER+) human breast cancer (MCF-7) progression after GEN withdrawal in athymic mice xenograft model was studied. Materials and methods Feeding studies were conducted to determine the estrogenic effect of diets on MCF-7 tumor growth: 1) implantation (19 weeks) and withdrawal (6 weeks) of 17β-estradiol (E2); 2) dietary GEN 500 and 750 ppm during treatment/withdrawal for 23/10 and 15/9 weeks, respectively; and, 3) dietary soy protein isolate (SPI) containing GEN 180 ppm for 31/9 weeks of treatment/withdrawal. MCF-7 tumors grew fast in the presence of E2 implantation and abruptly regressed completely after E2 withdrawal. At different rates, dietary GEN alone (500 and 750 ppm) and GEN (180 ppm)-containing SPI stimulated MCF-7 tumor growth. After removal of the stimulus diet, tumors induced by 750 ppm GEN, but not 500 ppm GEN or SPI, regressed completely. The protein expression of epidermal growth factor receptor 2 (HER2) was higher in the GEN- and SPI-induced non-regressing (GINR) tumors compared to MCF-7 and E2 controls. Conclusion Long-term consumption of low GEN doses (≤500 ppm) promotes MCF-7 tumor growth and results in GINR tumors with more aggressive and advanced growth phenotypes.