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

使用同源小鼠模型鉴定TIM基因家族，在该模型中TIM-1和TIM-2中的多态性被检测到。 TIM-3与Th 1-Th 2分化和变应原诱导的气道高反应性差异相关 (AHR)BALB/c小鼠与同源HBA小鼠之间的差异。我们的目标是了解蒂姆基因是如何调节 外周耐受性、适应性免疫应答和变态反应。我们已经证明TIM-1是一种重要的 作为T细胞的共刺激分子，TIM-1和TIM-4调节T细胞应答和 TIM-1和TIM-4是磷脂酰丝氨酸（PtdSer）的受体，磷脂酰丝氨酸是免疫耐受的关键分子。 凋亡细胞的识别和摄取。我们最近发现，在Th 1细胞上表达的TIM-3， APC也是PtdSer的受体，并且与哮喘相关的TIM-3的等位基因变体在结合方面不同， 到PtdSer。这些结果提示了TIM蛋白作为PtdSer受体的新范例，其通过调节 识别、清除和对凋亡细胞的反应，可以调节T细胞反应和诱导凋亡。 外周耐受性为了了解TIM蛋白识别PtdSer如何调节免疫应答，我们 提议： 具体目的1：确定TIM-4和TIM-3对APC与APC结合的功能性后果。 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对DC的影响， 包括（a）抗炎介质产生：IL-10、TGF-B、IDO;（B）共抑制因子的表达， 分子;和（c）共刺激分子的表达。我们将确定TIM-4的效果- 和TIM-3介导的凋亡细胞抗原对TReg和辅助性T细胞亚群发育的吞噬作用。 具体目标2。确定TIM等位基因变体在识别 磷脂酰丝氨酸、吞噬作用和T细胞活化。我们将确定表达HBA的细胞和 BALB/c小鼠TIM-1和TIM-3等位基因识别PtdSer和吞噬凋亡细胞的能力不同 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细胞增殖， 细胞活化和TReg发育，并比较BALB/c和HBA T细胞。 具体目的3：研究TIM-1和TIM-3等位基因变体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 在BALB/c和HBA小鼠中的凋亡细胞相关抗原的呈递中。 我们将确定TIM-1和TIM-3在调节BALB/c中AHR发展中的相对作用， HBA小鼠。 这些研究将大大增加我们对TIM在T细胞调节中的功能的了解， 反应和耐受性，并描述了一个新的和非常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.