Role of PD-L1 in Ocular Toxoplasmosis

描述（由申请人提供）：眼部弓形虫病是最常见的感染性视网膜炎，由弓形虫原虫感染引起。这种疾病是由静止的弓形虫组织囊肿在视网膜中重新激活而没有适当调节的免疫反应引起的。这种调节的一个组成部分是控制浸润的CD4 t细胞。但是，这些t细胞在弓形虫感染的视网膜中是如何被调节的尚不清楚。我们的假设是视网膜MHC II类和负性共刺激分子PD-L1（也称为B7H1）的表达在调节t细胞中起重要作用。为了支持这一假设，我们发现MHC II类和PD-L1在感染视网膜的浸润性白细胞和常驻视网膜神经细胞上都有表达。II类和PD-L1是功能性表达的，因为寄生虫感染的视网膜细胞可以抑制t细胞对弓形虫抗原的召回反应。最后，在弓形虫感染的动物中，PD-L1的缺失会导致严重的视网膜损伤。为了进一步验证我们的假设，提出了三个具体目标。特异性目标1将确定眼睛中t细胞抑制活性的局部位置。特异性Aim #2将定义眼部PD-L1表达细胞对t细胞的影响。在Specific Aim #3中，我们将确定常驻视网膜细胞是否可以作为活化t细胞的负调节因子。这些研究将为弓形虫感染以及其他基于免疫的视网膜疾病的视网膜免疫特权提供重要信息。

DESCRIPTION (provided by applicant): Ocular toxoplasmosis, which is caused by infections with the protozoan parasite Toxoplasma gondii, is the most common form of infectious retinitis. The disease is caused when quiescent Toxoplasma tissue cysts reactivate in the retina and a properly regulated immune response is not mounted. One component of this regulation is controlling infiltrating CD4 T-cells. But, how these T-cells are regulated in Toxoplasma infected retinas is unknown. Our hypothesis is that retinal expression of MHC Class II and the negative costimulatory molecule PD-L1 (also known as B7H1) are important in regulating the T-cells. In support of this hypothesis, we have discovered that MHC Class II and PD-L1 are expressed in the infected retina on both infiltrating leukocytes as well as resident neural retinal cells. Class II and PD-L1 were functionally expressed since cells from parasite-infected retinas could suppress T-cell recall responses to Toxoplasma antigen. Finally, loss of PD-L1 leads to significant retinal damage in Toxoplasma-infected animals. To further test our hypothesis, three specific aims are proposed. Specific Aim #1 will determine where in the eye the T-cell suppressive activity is localized. Specific Aim #2 will define the consequence of ocular PD-L1 expressing cells on T-cells. In Specific Aim #3, we will determine whether resident retinal cells can act at negative-regulators of activated T-cells. These studies will provide critical information regarding retinal immune privilege in Toxoplasma infections as well as other immune-based retinal diseases. PUBLIC HEALTH RELEVANCE: The goal of this application is to understand how the immune system is regulated when it responds to infections in the eye with the protozoan parasite Toxoplasma gondii from causing retinal disease. Understanding these mechanisms is important for the development of new treatments for this potentially blinding disease.