title: Transcription factor Bcl11b sustains iNKT1 and iNKT2 cell programs, restricts iNKT17 cell program, and governs iNKT cell survival.
abstract: Invariant natural killer T (iNKT) cells are innate-like T cells that recognize glycolipid antigens and play critical roles in regulation of immune responses. Based on expression of the transcription factors (TFs) Tbet, Plzf, and Rorγt, iNKT cells have been classified in effector subsets that emerge in the thymus, namely, iNKT1, iNKT2, and iNKT17. Deficiency in the TF Bcl11b in double-positive (DP) thymocytes has been shown to cause absence of iNKT cells in the thymus and periphery due to defective self glycolipid processing and presentation by DP thymocytes and undefined intrinsic alterations in iNKT precursors. We used a model of cre-mediated postselection deletion of Bcl11b in iNKT cells to determine its intrinsic role in these cells. We found that Bcl11b is expressed equivalently in all three effector iNKT subsets, and its removal caused a reduction in the numbers of iNKT1 and iNKT2 cells, but not in the numbers of iNKT17 cells. Additionally, we show that Bcl11b sustains subset-specific cytokine production by iNKT1 and iNKT2 cells and restricts expression of iNKT17 genes in iNKT1 and iNKT2 subsets, overall restraining the iNKT17 program in iNKT cells. The total numbers of iNKT cells were reduced in the absence of Bcl11b both in the thymus and periphery, associated with the decrease in iNKT1 and iNKT2 cell numbers and decrease in survival, related to changes in survival/apoptosis genes. Thus, these results extend our understanding of the role of Bcl11b in iNKT cells beyond their selection and demonstrate that Bcl11b is a key regulator of iNKT effector subsets, their function, identity, and survival.
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610;
authors.forename: Mohammad Nizam
authors.initials: MN
authors.lastname: Uddin
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610;
authors.forename: Dil Afroz
authors.initials: DA
authors.lastname: Sultana
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610;
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Lorentsen
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610;
authors.forename: Jonathan J
authors.initials: JJ
authors.lastname: Cho
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610;
authors.forename: Mariana E
authors.initials: ME
authors.lastname: Kirst
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610;
authors.forename: Mark L
authors.initials: ML
authors.lastname: Brantly
authors.affiliation: Center for Immunology and Microbial Disease, Albany Medical Center, Albany, NY 12208;
authors.forename: Danielle
authors.initials: D
authors.lastname: Califano
authors.affiliation: Department of Pediatrics, Rutgers Robert Wood Johnson Medical School and The Child Health Institute of New Jersey, New Brunswick, NJ 08901.
authors.forename: Derek B
authors.initials: DB
authors.lastname: Sant'Angelo
authors.affiliation: Division of Pulmonary Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610; Dorina.Avram@medicine.ufl.edu.
authors.forename: Dorina
authors.initials: D
authors.lastname: Avram
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D005786:Gene Expression Regulation; D051379:Mice; D055611:Natural Killer T-Cells / Q000502:physiology*; D039942:Neuropilin-1 / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D013950:Thymus Gland / Q000276:immunology; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: C511143:Bcl11b protein, mouse; D016207:Cytokines; D012097:Repressor Proteins; D025521:Tumor Suppressor Proteins; D039942:Neuropilin-1
keywords: iNKT cell program; iNKT1 effector cells; iNKT17 effector cells; iNKT2 effector cells; transcription factor Bcl11b