TIM recognition of PtdSer on apoptotic cells and the regulation of immunity

TIM基因家族是使用同源小鼠模型鉴定的，在该模型中，TIM-1和TIM-1基因的多态 TIM-3与Th1-Th2分化差异和变应原诱导的呼吸道高反应性有关 (AHR)在BALB/c小鼠和同源HBA小鼠之间。我们的目标是了解Tim基因是如何调控的 外周耐受性、适应性免疫反应和过敏。我们已经证明TIM-1是一种重要的 T细胞共刺激分子TIM-1和TIM-4调节T细胞反应和TIM-4 TIM-1和TIM-4是磷脂酰丝氨酸(PtdSer)的受体，磷脂酰丝氨酸是PtdSer的关键分子 对凋亡细胞的识别和吸收。我们最近发现TIM-3，表达在Th1细胞和 APC，也是PtdSer的受体，与哮喘相关的TIM-3的等位基因变体在结合方面有所不同 致PtdSer。这些结果提示了一种新的TIM蛋白作为PtdSer受体的范例，即通过调节 对凋亡细胞的识别、清除和反应，可以调节T细胞的反应和诱导 外围设备容忍度。为了了解PtdSer的Tim蛋白质识别如何调节免疫反应，我们 建议： 具体目标1：确定TIM-4和TIM-3对APC结合的功能影响 磷脂酰丝氨酸对凋亡细胞的影响。我们将研究凋亡细胞吞噬DC和 巨噬细胞包括：(A)抗炎介质的产生：IL-10、转化生长因子-β、IDO；(B)共抑制的表达 以及(C)共刺激分子的表达。我们将确定TIM-4的效果- TIM-3介导的凋亡细胞抗原对Treg和T辅助细胞亚群发育的吞噬作用。 特定目的2.确定TIM等位基因变异体的结构/功能关系 磷脂酰丝氨酸、吞噬作用和T细胞活化。我们将确定表达HBA和HBA的细胞 TIM-1和TIM-3的Balb/c等位基因识别PtdSer和吞噬细胞凋亡的能力不同 细胞。我们将确定凋亡细胞上的PtdSer与T细胞上的TIM-1和TIM-3的结合如何调节T细胞 细胞活化和Treg发育，并比较BALB/c和Hba T细胞。 特异性目标3：研究TIM-1和TIM-3等位基因变异在免疫应答中的体内作用 和外周耐受性的调节。我们将比较TIM-3通路在清除 BALB/c和HBA小鼠体内的凋亡细胞和凋亡细胞相关抗原的呈递。 我们将确定TIM-1和TIM-3在调节AHR在BALB/c和BALB/c中的相对作用。 HBA小鼠。 这些研究将极大地加深我们对TIMs在T细胞调节中的功能的理解 反应和耐受性，并表征了一个新的和极其重要的哮喘易感基因家族。

The TIM gene family was identified using a congenic mouse model in which polymorphisms in TIM-1 and TIM-3 were associated with differences in Th1-Th2 differentiation and allergen-induced airway hyperreactivity (AHR) between BALB/c and congenic HBA mice. Our goal is to understand how the Tim genes regulate peripheral tolerance, adaptive immune responses, and allergy. We have shown that TIM-1 is an important costimulatory molecule for T cells, that TIM-1 and TIM-4 regulate T cell responses and the development of tolerance, and that TIM-1 and TIM-4 are receptors for phosphatidylserine (PtdSer), a key molecule for recognition and uptake of apoptotic cells. We have recently found that TIM-3, expressed on Th1 cells and APC, is also a receptor for PtdSer and that the allelic variants of TIM-3 associated with asthma differ in binding to PtdSer. These results suggest a new paradigm for TIM proteins as PtdSer receptors that by regulating the recognition, clearance, and response to apoptotic cells, can regulate T cell responses and the induction of peripheral tolerance. To understand how TIM protein recognition of PtdSer regulates immune responses, we propose to: Specific Aim 1: Determine the functional consequences of TIM-4 and TIM-3 on APC binding to phosphatidylserine on apoptotic cells. We will examine effects of apoptotic cell engulfment on DCs and macrophages including (a) anti-inflammatory mediator production: IL-10, TGF-B, IDO; (b) expression of co-inhibitory molecules; and (c) expression of co-stimulatory molecules. We will determine the effects of TIM-4- and TIM-3 mediated phagocytosis of apoptotic cell antigen on TReg and T helper subset development. Specific Aim 2. Determine the structure/function relationship of TIM allelic variants on recognition of phosphatidylserine, phagocytosis, and T cell activation. We will determine if cells expressing HBA and BALB/c alleles of TIM-1 and TIM-3 have different capacities to recognize PtdSer and phagocytose apoptotic cells. We will determine how binding of PtdSer on an apoptotic cell to TIM-1 and TIM-3 on a T cell regulates T cell activation and TReg development, and compare BALB/c and HBA T cells. Specific Aim 3: Investigate the in vivo role of TIM-1 and TIM-3 allelic variants in immune responses and regulation of peripheral tolerance. We will compare the roles of the TIM-3 pathway in clearance of apoptotic cells in vivo and in the presentation of apoptotic cell-associated antigen in BALB/c and HBA mice. We will determine the relative roles of TIM-1 and TIM-3 in regulating the development of AHR in BALB/c and HBA mice. These studies will greatly increase our understanding of the function of TIMs in the regulation of T cell responses and tolerance, and characterize a novel and extremely important asthma susceptibility gene family.