BCL11B is positioned upstream of PLZF and RORγt to control thymic development of mucosal-associated invariant T cells and MAIT17 program
Theodore T. Drashansky,
Eric Y. Helm,
Nina Curkovic,
Jaimee Cooper,
Pingyan Cheng,
Xianghong Chen,
Namrata Gautam,
Lingsong Meng,
Alexander J. Kwiatkowski,
William O. Collins,
Benjamin G. Keselowsky,
Derek Sant’Angelo,
Zhiguang Huo,
Weizhou Zhang,
Liang Zhou,
Dorina Avram
Affiliations
Theodore T. Drashansky
Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
Eric Y. Helm
Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
Nina Curkovic
Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
Jaimee Cooper
Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
Pingyan Cheng
Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr, Tampa, FL 33612, USA
Xianghong Chen
Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr, Tampa, FL 33612, USA
Namrata Gautam
Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr, Tampa, FL 33612, USA
Lingsong Meng
Department of Biostatistics, College of Medicine, College of Public Health & Health Professions, University of Florida, Gainesville, FL 32611, USA
Alexander J. Kwiatkowski
J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA
William O. Collins
Department of Otolaryngology, College of Medicine, University of Florida, Gainesville, FL 32605, USA
Benjamin G. Keselowsky
J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, FL 32611, USA
Derek Sant’Angelo
Department of Pediatrics, The Child Health Institute of NJ, Robert Wood Johnson Medical School, New Brunswick, NJ 08903, USA
Zhiguang Huo
Department of Biostatistics, College of Medicine, College of Public Health & Health Professions, University of Florida, Gainesville, FL 32611, USA
Weizhou Zhang
Department of Pathology, Immunology and Laboratory Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA; UF Health Cancer Center, Gainesville, FL 32610, USA
Liang Zhou
UF Health Cancer Center, Gainesville, FL 32610, USA; Department of Infectious Diseases and Immunology, College of Veterinary Medicine, University of Florida, Gainesville, FL 32608, USA
Dorina Avram
Department of Anatomy and Cell Biology, College of Medicine, University of Florida, Gainesville, FL 32610, USA; Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr, Tampa, FL 33612, USA; UF Health Cancer Center, Gainesville, FL 32610, USA; Corresponding author
Summary: Mucosal-associated invariant T (MAIT) cells recognize microbial riboflavin metabolites presented by MR1 and play role in immune responses to microbial infections and tumors. We report here that absence of the transcription factor (TF) Bcl11b in mice alters predominantly MAIT17 cells in the thymus and further in the lung, both at steady state and following Salmonella infection. Transcriptomics and ChIP-seq analyses show direct control of TCR signaling program and position BCL11B upstream of essential TFs of MAIT17 program, including RORγt, ZBTB16 (PLZF), and MAF. BCL11B binding at key MAIT17 and at TCR signaling program genes in human MAIT cells occurred mostly in regions enriched for H3K27Ac. Unexpectedly, in human MAIT cells, BCL11B also bound at MAIT1 program genes, at putative active enhancers, although this program was not affected in mouse MAIT cells in the absence of Bcl11b. These studies endorse BCL11B as an essential TF for MAIT cells both in mice and humans.
