Browsing by Subject "Blimp1"

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    Bcl6 promotes follicular helper T-cell differentiation and PD-1 expression in a Blimp1-independent manner in mice
    (Wiley, 2017-07) Xie, Markus M.; Koh, Byung-Hee; Hollister, Kristin; Wu, Hao; Sun, Jie; Kaplan, Mark H.; Dent, Alexander L.; Department of Microbiology and Immunology, IU School of Medicine
    The transcription factors Bcl6 and Blimp1 have opposing roles in the development of the follicular helper T (TFH) cells: Bcl6 promotes and Blimp1 inhibits TFH-cell differentiation. Similarly, Bcl6 activates, while Blimp1 represses, expression of the TFH-cell marker PD-1. However, Bcl6 and Blimp1 repress each other's expression, complicating the interpretation of the regulatory network. Here we sought to clarify the extent to which Bcl6 and Blimp1 independently control TFH-cell differentiation by generating mice with T-cell specific deletion of both Bcl6 and Blimp1 (double conditional KO [dcKO] mice). Our data indicate that Blimp1 does not control TFH-cell differentiation independently of Bcl6. However, a population of T follicular regulatory (TFR) cells developed independently of Bcl6 in dcKO mice. We have also analyzed regulation of IL-10 and PD-1, two genes controlled by both Bcl6 and Blimp1, and observed that Bcl6 regulates both genes independently of Blimp1. We found that Bcl6 positively regulates PD-1 expression by inhibiting the ability of T-bet/Tbx21 to repress Pdcd1 transcription. Our data provide a novel mechanism for positive control of gene expression by Bcl6, and illuminate how Bcl6 and Blimp1 control TFH-cell differentiation.
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    Blimp1 Prevents Methylation of Foxp3 and Loss of Regulatory T Cell Identity at Sites of Inflammation
    (Elsevier, 2019-02-12) Garg, Garima; Muschaweckh, Andreas; Moreno, Helena; Vasanthakumar, Ajithkumar; Floess, Stefan; Lepennetier, Gildas; Oellinger, Rupert; Zhan, Yifan; Regen, Tommy; Hiltensperger, Michael; Peter, Christian; Aly, Lilian; Knier, Benjamin; Palam, Lakshmi Reddy; Kapur, Reuben; Kaplan, Mark H.; Waisman, Ari; Rad, Roland; Schotta, Gunnar; Huehn, Jochen; Kallies, Axel; Korn, Thomas; Pediatrics, School of Medicine
    Foxp3+ regulatory T (Treg) cells restrict immune pathology in inflamed tissues; however, an inflammatory environment presents a threat to Treg cell identity and function. Here, we establish a transcriptional signature of central nervous system (CNS) Treg cells that accumulate during experimental autoimmune encephalitis (EAE) and identify a pathway that maintains Treg cell function and identity during severe inflammation. This pathway is dependent on the transcriptional regulator Blimp1, which prevents downregulation of Foxp3 expression and "toxic" gain-of-function of Treg cells in the inflamed CNS. Blimp1 negatively regulates IL-6- and STAT3-dependent Dnmt3a expression and function restraining methylation of Treg cell-specific conserved non-coding sequence 2 (CNS2) in the Foxp3 locus. Consequently, CNS2 is heavily methylated when Blimp1 is ablated, leading to a loss of Foxp3 expression and severe disease. These findings identify a Blimp1-dependent pathway that preserves Treg cell stability in inflamed non-lymphoid tissues.