The function of the NKT cell determinant, PLZF, in mucosal lymphocytes.

描述（由申请人提供）：我们最近发现，单一转录PLZF控制固有效应子功能的发展，所述固有效应子功能是不变的自然杀伤T细胞（iNKT细胞）的特征。iNKT细胞是对感染极其有效的“第一反应者”。先天性T细胞的攻击性也使它们成为免疫治疗的有吸引力的靶点;一些临床试验正在进行中。有趣的是，iNKT细胞具有拮抗功能，因为它们都显示出在某些情况下增强免疫力，但在其他情况下抑制自身免疫力。事实上，至少有一份已发表的报告显示，iNKT细胞的特异性激活可保护小鼠免受结肠炎的侵害。 在全身免疫系统中，先天性T细胞决定簇PLZF的表达几乎仅限于iNKT细胞。例如，转录因子不在静息、活化或分化的常规T细胞、NK细胞、B细胞、巨噬细胞、嗜中性粒细胞或嗜酸性粒细胞中表达。与此形成鲜明对比的是，在肠道中，PLZF表达在各种不同的淋巴细胞，包括CD 8aa T细胞，CD 4CD 8a T细胞和？d T细胞。有趣的是，许多CD 8 T细胞仅限于MHC Ib类（非经典）MHC分子。最重要的是，从PLZF缺陷小鼠肠道分离的CD 8aa T细胞产生大量的IFN-？激活后。同样的淋巴细胞收获野生型小鼠产生很少的干扰素？ 总而言之，这些结果强烈表明PLZF表达在维持肠道免疫调节和预防可能导致慢性炎症的Th 1应答中起主导作用。他们还表明，PLZF表达可能赋予先天的细胞毒性能力，b型a和？d IEL，其对于感染和转化的上皮细胞的清除以及因此对于维持上皮屏障的完整性是必需的。 我们提出了一系列的实验，旨在更好地了解PLZF表达的后果在正常和病理条件下的肠粘膜淋巴细胞。 最近，我们发现一个单一的转录因子，PLZF，控制的T细胞亚群称为自然杀伤T细胞（NKT细胞）的功能。NKT细胞是非常有趣的，因为它们是非常有效的感染第一反应者。它们还被证明可以通过调节免疫系统其他细胞的功能来控制自身免疫。我们的初步数据强烈表明，表达PLZF的淋巴细胞在维持肠道免疫调节和预防可能导致慢性炎症的免疫反应类型方面发挥着重要作用。我们提出的研究将为粘膜免疫提供新的见解，并很可能为治疗干预提供新的靶点。

DESCRIPTION (provided by applicant): We have recently discovered that a single transcription, PLZF, controls the development of the innate effector functions that are characteristic of invariant natural killer T cells (iNKT cells). iNKT cells are extremely potent "first responders" to infection. The aggressive nature of innate T cells has also made them attractive targets for immunotherapy; several clinical trials are in progress. Intriguingly, iNKT cells have antagonistic functions, since they have both been shown to enhance immunity in some circumstances, but to suppress autoimmunity in others. Indeed, at least one published report shows that specific activation of iNKT cells protects mice against colitis. In the systemic immune system, expression of the innate T cell determinant, PLZF, is nearly exclusively restricted to iNKT cells. For example, the transcription factor is not expressed in resting, activated or differentiated conventional T cells, NK cells, B cells, macrophages, neutrophils or eosinophils. In sharp contrast, in the gut, PLZF is expressed in a variety of different lymphocytes including CD8aa T cells, CD4CD8a T cells and ?d T cells. Interestingly, many of the CD8 T cells are restricted to MHC class Ib (non-classical) MHC molecules. Most significantly, CD8aa T cells isolated from the guts of PLZF deficient mice produced large amounts of IFN-? following activation. The same lymphocytes harvested from wild type mice produced little IFN? Altogether, these results strongly suggest a dominant role for PLZF expression in the maintenance of the immunoregulatory tone of the intestine and in the prevention of Th1 responses that may lead to chronic inflammation. They also suggest that PLZF expression may be conferring the innate cytotoxic capabilities to type-b a¿ and ?d IELs which is essential for the clearance of infected and transformed epithelial cell and, therefore, for maintaining the integrity of the epithelial barrier. We propose a series of experiments aimed at gaining a better understanding of the consequences of PLZF expression in lymphocytes in the intestinal mucosa in normal and pathological conditions. Recently we discovered that a single transcription factor, PLZF, controls the functions of a subpopulation of T cells known as Natural Killer T cells (NKT cells). NKT cells are of great interest because they are very potent first responders to infection. They also have been shown to control autoimmunity by modulating the functions of other cells of the immune system. Our preliminary data strongly suggests that lymphocytes expressing PLZF play a major role in maintaining the immunoregulatory tone of the intestine and in the preventing the type of immune responses that may lead to chronic inflammation. Our proposed studies will offer novel insight into mucosal immunity and very likely will provide new targets for therapeutic intervention.