SOX4 and SOX13 control early steps of invariant NKT cell differentiation

描述(由申请人提供)：表达典型的V？14-J？18TCR的不变NKT(INKT)细胞是对潜在损害宿主的改变环境的早期免疫反应的中心。这种快速反应决定了不同的淋巴系和髓系细胞亚群随后的活动。因此，靶向调节iNKT细胞已成为治疗炎症性疾病以及增强对肿瘤和疫苗的免疫力的潜在方法。INKT细胞在非经典MHC I类分子CD1d的背景下识别脂类抗原。INKT细胞的快速效应能力，通常被称为“先天类”反应，是在胸腺内编程的，与传统T细胞介导的获得性免疫有根本的不同。INKT细胞功能的胸腺内编程已被证明依赖于规范的TCR信号，由此推论，TCR信号承诺了T细胞的共同前体，使其成为先天的类似细胞。然而，iNKT细胞与其他先天类淋巴细胞如T细胞有共同的分子特征，控制iNKT细胞发育的基因受TCR以外的信号调控。我们观察到，缺乏高迁移率组盒(HMG)转录因子(TFS)Sox4或Sox13的小鼠在iNKT和先天样T细胞亚群的产生方面受到损害，但不影响传统的适应性T细胞。这两种因子都是在TCR基因重排之前表达的，在其他类型的细胞中，HMG因子的组合活性决定了细胞的谱系特征和功能。Sox13仅在iNKT和？？TCR+胸腺细胞亚群中表达，在效应器功能编程期间和胸腺出口之前。SOX13也在一半的早期T细胞前体细胞中表达，这增加了Sox13+祖细胞可能偏向于产生表达？？TCR或？？TCR的先天效应器的可能性。为了测试这种替代的iNKT分化模式，我们培育并验证了Sox13报告小鼠。这一建议将确定Sox13和Sox4是否在先天淋巴谱系中发挥作用，决定了iNKT细胞的快速效应器潜力。

DESCRIPTION (provided by applicant): Invariant NKT (iNKT) cells expressing the canonical V?14-J?18 TCR are central to early immune responses to altered environments potentially damaging to the host. This fast response conditions subsequent activities of diverse lymphoid and myeloid cell subsets. Thus, targeted modulations of iNKT cells have emerged as a potential approach to treat inflammatory disorders as well as enhancing immunity to tumors and vaccines. iNKT cells recognize lipid antigens in the context of the non-classical MHC Class I molecule CD1d. The rapid effector capabilities of iNKT cells, often referred to as "innate-like" responses, are programmed intrathymically and are fundamentally different from the adaptive immunity mediated by the conventional ??T cells. The intrathymic programming of iNKT cell function has been shown to dependent on the signaling of the canonical TCR, and by extension, it has been assumed that TCR signals commit a common precursor of ??T cells to become innate like. However, iNKT cells share molecular features with other innate-like lymphocytes such as ??T cells and genes that control iNKT cell development are modulated by signals other than TCR. We observed that mice lacking the High Mobility Group box (HMG) transcription factors (TFs) Sox4 or Sox13 are impaired in the generation of iNKT and innate-like ??T cell subsets, but not conventional adaptive ??T cells. Both TFs are expressed prior to Tcr gene rearrangements, and in other cell types, combinatorial activities of HMG TFs dictate cell lineage identity and function. Sox13 is exclusively expressed in iNKT and ??TCR+ thymocyte subsets during the programming of effector function and prior to thymic egress. Sox13 is also expressed in half of early T cell progenitors, raising the possibility that Sox13+ progenitors may be biased to generate innate-like effectors expressing either ??TCR or ??TCR. To test this alternate mode of iNKT differentiation, we have developed and validated Sox13 reporter mice. This proposal will determine whether Sox13 and Sox4 function in an innate lymphoid lineage committed precursor to program the rapid effector potential of iNKT cells.