Uddin Mohammad Nizam, Sultana Dil Afroz, Lorentsen Kyle J, Cho Jonathan J, Kirst Mariana E, Brantly Mark L, Califano Danielle, Sant'Angelo Derek B, Avram Dorina
Division of Pulmonary Medicine, Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610;
Center for Immunology and Microbial Disease, Albany Medical Center, Albany, NY 12208;
Proc Natl Acad Sci U S A. 2016 Jul 5;113(27):7608-13. doi: 10.1073/pnas.1521846113. Epub 2016 Jun 21.
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.
不变自然杀伤T（iNKT）细胞是一类天然样T细胞，可识别糖脂抗原，并在免疫反应调节中发挥关键作用。基于转录因子（TFs）Tbet、Plzf和Rorγt的表达情况，iNKT细胞已被分类为在胸腺中出现的效应子亚群，即iNKT1、iNKT2和iNKT17。研究表明，双阳性（DP）胸腺细胞中TF Bcl11b的缺陷会导致胸腺和外周中iNKT细胞缺失，这是由于DP胸腺细胞自身糖脂加工和呈递缺陷以及iNKT前体中未明确的内在改变所致。我们使用了一种在iNKT细胞中通过cre介导的Bcl11b选择后缺失模型，以确定其在这些细胞中的内在作用。我们发现Bcl11b在所有三个效应性iNKT亚群中表达相当，去除它会导致iNKT1和iNKT2细胞数量减少，但不会导致iNKT17细胞数量减少。此外，我们表明Bcl11b维持iNKT1和iNKT2细胞产生亚群特异性细胞因子，并限制iNKT1和iNKT2亚群中iNKT17基因的表达，总体上抑制iNKT细胞中的iNKT17程序。在胸腺和外周中，缺乏Bcl11b时iNKT细胞总数减少，这与iNKT1和iNKT2细胞数量减少以及存活率降低有关，而存活率降低与存活/凋亡基因的变化有关。因此，这些结果扩展了我们对Bcl11b在iNKT细胞中作用的理解，超出了其选择过程，并表明Bcl11b是iNKT效应子亚群、其功能、特性和存活的关键调节因子。
