Whiteside, S.K. (Sarah K.)

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2020 - 20222

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    A distal enhancer at risk locus 11q13.5 promotes suppression of colitis by Treg cells
    (Nature Research, 2020) Imianowski, C.J. (Charlotte J.); Grant, F.M. (Francis M.); Kuo, P. (Paula); Sadiyah, F. (Firas); Vardaka, P. (Panagiota); Lozano-Moreda, T. (Teresa); Yang, J. (Jie); Lugli, E. (Enrico); Roychoudhuri, R. (Rahul); Nasrallah, R. (Rabab); Bossini-Castillo, L. (Lara); Dogan, M. (Mikail); Placek, L. (Lindsey); Kozhaya, L. (Lina); Whiteside, S.K. (Sarah K.); Mumbach, M.R. (Maxwell R.); Glinos, D. (Dafni); Whyte, C.E. (Carly E.); Fujita, T. (Toshitsugu); Fujii, H. (Hodaka); Liston, A. (Adrian); Andrews, S. (Simon); Cozzani, A. (Adeline); Mitra, S. (Suman); Chang, H.Y. (Howard Y.); Unutmaz, D. (Derya); Trynka, G. (Gosia)
    Genetic variations underlying susceptibility to complex autoimmune and allergic diseases are concentrated within noncoding regulatory elements termed enhancers1. The functions of a large majority of disease-associated enhancers are unknown, in part owing to their distance from the genes they regulate, a lack of understanding of the cell types in which they operate, and our inability to recapitulate the biology of immune diseases in vitro. Here, using shared synteny to guide loss-of-function analysis of homologues of human enhancers in mice, we show that the prominent autoimmune and allergic disease risk locus at chromosome 11q13.52,3,4,5,6,7 contains a distal enhancer that is functional in CD4+ regulatory T (Treg) cells and required for Treg-mediated suppression of colitis. The enhancer recruits the transcription factors STAT5 and NF-κB to mediate signal-driven expression of Lrrc32, which encodes the protein glycoprotein A repetitions predominant (GARP). Whereas disruption of the Lrrc32 gene results in early lethality, mice lacking the enhancer are viable but lack GARP expression in Foxp3+ Treg cells, which are unable to control colitis in a cell-transfer model of the disease. In human Treg cells, the enhancer forms conformational interactions with the promoter of LRRC32 and enhancer risk variants are associated with reduced histone acetylation and GARP expression. Finally, functional fine-mapping of 11q13.5 using CRISPR-activation (CRISPRa) identifies a CRISPRa-responsive element in the vicinity of risk variant rs11236797 capable of driving GARP expression. These findings provide a mechanistic basis for association of the 11q13.5 risk locus with immune-mediated diseases and identify GARP as a potential target in their therapy.
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    BACH2 restricts NK cell maturation and function, limiting immunity to cancer metastasis
    (Rockefeller University Press, 2022) Imianowski, C.J. (Charlotte J.); Whiteside, S.K. (Sarah K.); Lozano-Moreda, T. (Teresa); Evans, A.C. (Alexander C.); Benson, J.D. (Jayme D.); Courreges, C.J.F. (Christina J.F.); Sadiyah, F. (Firas); Lau, C.M. (Colleen M.); Zandhuis, N.D. (Nordin D.); Grant, F.M. (Francis M.); Schuijs, M.J. (Martijn J.); Vardaka, P. (Panagiota); Kuo, P. (Paula); Soilleux, E.J. (Elizabeth J.); Yang, J. (Jie); Sun, J.C. (Joseph C.); Kurosaki, T. (Tomohiro); Okkenhaug, K. (Klaus); Halim, T.Y.F. (Timotheus Y.F.); Roychoudhuri, R. (Rahul)
    Natural killer (NK) cells are critical to immune surveillance against infections and cancer. Their role in immune surveillance requires that NK cells are present within tissues in a quiescent state. Mechanisms by which NK cells remain quiescent in tissues are incompletely elucidated. The transcriptional repressor BACH2 plays a critical role within the adaptive immune system, but its function within innate lymphocytes has been unclear. Here, we show that BACH2 acts as an intrinsic negative regulator of NK cell maturation and function. BACH2 is expressed within developing and mature NK cells and promotes the maintenance of immature NK cells by restricting their maturation in the presence of weak stimulatory signals. Loss of BACH2 within NK cells results in accumulation of activated NK cells with unrestrained cytotoxic function within tissues, which mediate augmented immune surveillance to pulmonary cancer metastasis. These findings establish a critical function of BACH2 as a global negative regulator of innate cytotoxic function and tumor immune surveillance by NK cells.