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Critical role of IRF1 and BATF in forming chromatin landscape during type 1 regulatory cell differentiation

Nature Immunology volume 18, pages 412421 (2017) | Download Citation


Type 1 regulatory T cells (Tr1 cells) are induced by interleukin-27 (IL-27) and have critical roles in the control of autoimmunity and resolution of inflammation. We found that the transcription factors IRF1 and BATF were induced early on after treatment with IL-27 and were required for the differentiation and function of Tr1 cells in vitro and in vivo. Epigenetic and transcriptional analyses revealed that both transcription factors influenced chromatin accessibility and expression of the genes required for Tr1 cell function. IRF1 and BATF deficiencies uniquely altered the chromatin landscape, suggesting that these factors serve a pioneering function during Tr1 cell differentiation.

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We thank D. Kozoriz (Evergrande Center) for cell sorting, F. Quintana (Harvard Medical School) for providing AhR mutant mice, the New York University Langone Medical Center genomics core (A. Heguy and P. Zappile) for help with sequencing, and the Genome Technology Center (at the Laura and Isaac Perlmutter Cancer Center supported by the Cancer Center Support Grant P30CA016087) for help with sequencing. We are most thankful to M. Collins for advice and editing of the manuscript. This work was supported by the US national Institutes of Health (R01 NS 030843, R01 NS 045937, P01 AI073748, P01 NS076410, P01 AI039671 and 5P01 AI056299-10 to V.K.K.; P01NS076410 to D.L. and M.P.; 5T32AI100853 to M.P.; 1R01-DK103358-01 to E.R.M., R.B. and D.L.; and 1R01-GM112192-01 to R.B.), the National Multiple Sclerosis Society (K.K.), Marie Skłodowska-Curie Actions (of the European Commission / Research Executive Agency), grant agreement number 302915, Marie Curie International Outgoing Fellowship (K.K.), the National Science Foundation (IOS-1126971 to R.B.), the DBT-Wellcome Trust (IA/I/12/1/500524 to A.A.), the Klarman Cell Observatory at the Broad Institute (A.R.), the Howard Hughes Medical Institute (A.R.) and the National Cancer Institute (Koch Institute Support (P30-CA14051 to A.R.).

Author information


  1. Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts, USA.

    • Katarzyna Karwacz
    • , Asaf Madi
    •  & Vijay K Kuchroo
  2. Center for Computational Biology, Flatiron Institute, Simons Foundation, New York, New York, USA.

    • Emily R Miraldi
    • , Aaron Watters
    • , Nicholas Carriero
    •  & Richard Bonneau
  3. Skirball Institute for Biomolecular Medicine, New York University School of Medicine, New York, New York, USA.

    • Emily R Miraldi
    • , Maria Pokrovskii
    •  & Dan Littman
  4. Department of Electrical Engineering and Computer Science and Center for Computational Biology, University of California, Berkeley, Berkeley, California, USA.

    • Nir Yosef
  5. Broad Institute of the Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA.

    • Ivo Wortman
    •  & Aviv Regev
  6. Department of Biology, New York University, New York, New York, USA.

    • Xi Chen
    •  & Richard Bonneau
  7. Center for Human Microbial Ecology, Translational Health Science and Technology Institute (an autonomous institute of Department of Biotechnology, Govt. of India), NCR Biotech Science Cluster, Faridabad, India.

    • Amit Awasthi


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K.K. planned, performed and analyzed all of the biological experiments and wrote the manuscript. E.R.M. designed and actuated computational analyses for RNA-seq/ATAC-seq, and contributed to the interpretation of the results and writing of the manuscript. M.P. prepared ATAC-seq libraries, coordinated sequencing with the NYUMC genomics core, and contributed to interpretation of the results and general discussion. A.M., N.Y., X.C., A.W. and N.C. contributed to computational analysis. I.W. prepared RNA-seq libraries and coordinated sequencing. A.A. provided reagents and advice. A.R. developed and undertook transcriptional analysis of IL-27-induced Tr1 cells. R.B. contributed to computational analysis, interpretation of the results and writing of the manuscript. D.L. advised and provided insight into the analysis of ATAC-seq and RNA-seq analysis. V.K.K. supervised the study and wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Vijay K Kuchroo.

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