Browsing by Author "Kallies, Axel"

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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.
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    CXCR5+ follicular cytotoxic T cells control viral infection in B cell follicles
    (Nature, 2016) Leong, Yew Ann; Chen, Yaping; Ong, Hong Sheng; Wu, Di; Man, Kevin; Deleage, Claire; Minnich, Martina; Meckiff, Benjamin J.; Wei, Yunbo; Hou, Zhaohua; Zotos, Dimitra; Fenix, Kevin A.; Atnerkar, Anurag; Preston, Simon; Chipman, Jeffrey G.; Beilman, Greg J.; Allison, Cody C.; Sun, Lei; Wang, Peng; Xu, Jiawei; Toe, Jesse G.; Lu, Hao K.; Tao, Yong; Palendira, Umaimainthan; Dent, Alexander L.; Landay, Alan L.; Pellegrini, Marc; Comerford, Iain; McColl, Shaun R.; Schacker, Timothy W.; Long, Heather M.; Estes, Jacob D.; Busslinger, Meinrad; Belz, Gabrielle T.; Lewin, Sharon R.; Kallies, Axel; Yu, Di; Department of Microbiology and Immunology, IU School of Medicine
    During unresolved infections, some viruses escape immunological control and establish a persistant reservoir in certain cell types, such as human immunodeficiency virus (HIV), which persists in follicular helper T cells (TFH cells), and Epstein-Barr virus (EBV), which persists in B cells. Here we identified a specialized group of cytotoxic T cells (TC cells) that expressed the chemokine receptor CXCR5, selectively entered B cell follicles and eradicated infected TFH cells and B cells. The differentiation of these cells, which we have called 'follicular cytotoxic T cells' (TFC cells), required the transcription factors Bcl6, E2A and TCF-1 but was inhibited by the transcriptional regulators Blimp1, Id2 and Id3. Blimp1 and E2A directly regulated Cxcr5 expression and, together with Bcl6 and TCF-1, formed a transcriptional circuit that guided TFC cell development. The identification of TFC cells has far-reaching implications for the development of strategies to control infections that target B cells and TFH cells and to treat B cell–derived malignancies.