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

描述(申请人提供)：我们最近发现，一个单一的转录，PLZF，控制着固有效应功能的发展，这是不变的自然杀伤T细胞(iNKT细胞)的特征。INKT细胞对感染具有极强的“第一反应”能力。与生俱来的T细胞的侵略性也使它们成为免疫治疗的有吸引力的目标；几项临床试验正在进行中。有趣的是，iNKT细胞具有拮抗功能，因为它们都被证明在某些情况下增强免疫力，但在另一些情况下抑制自身免疫力。事实上，至少有一份发表的报告表明，iNKT细胞的特定激活可以保护小鼠免受结肠炎的侵袭。 在系统免疫系统中，先天T细胞决定簇PLZF的表达几乎仅限于iNKT细胞。例如，转录因子在静息、激活或分化的常规T细胞、NK细胞、B细胞、巨噬细胞、中性粒细胞或嗜酸性粒细胞中不表达。与之形成鲜明对比的是，在肠道中，PLZF在多种不同的淋巴细胞中表达，包括CD8aa T细胞、CD4CD8a T细胞和？dT细胞。有趣的是，许多CD8T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CD8aa T细胞产生大量的干扰素？在激活之后。野生型小鼠的淋巴细胞产生的干扰素很少。 总之，这些结果强烈表明PLZF的表达在维持肠道的免疫调节基调和防止可能导致慢性炎症的Th1反应方面发挥了主导作用。他们还提示，PLZF的表达可能赋予了b型和d型IEL固有的细胞毒能力，这对于清除感染和转化的上皮细胞，从而维持上皮屏障的完整性是必不可少的。 我们提出了一系列实验，旨在更好地了解PLZF在正常和病理条件下肠粘膜淋巴细胞中表达的后果。 最近我们发现，一个单一的转录因子PLZF控制着一种称为自然杀伤T细胞(NKT细胞)的T细胞亚群的功能。NKT细胞之所以引起人们的极大兴趣，是因为它们是非常强大的感染第一反应者。它们还被证明通过调节免疫系统其他细胞的功能来控制自身免疫。我们的初步数据有力地表明，表达PLZF的淋巴细胞在维持肠道的免疫调节张力和防止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.