Pregnancy and T cell homeostasis

描述(由申请者提供)：在我们对T细胞稳态及其在组织特异性耐受中的作用的理解上仍有很大的差距。这项申请通过母体对胎儿和胎盘上表达的抗原免疫的例子来解决这些问题。母体对胎儿的耐受被认为依赖于几种机制，包括限制母胎界面上的细胞运输，以及抑制或删除胎儿抗原特异性T细胞。然而，其他人和我们已经证明，母亲和胎儿之间可能发生细胞运输，并且对胎儿抗原的免疫力可以在怀孕期间产生。这种免疫的结果通常不是胎儿排斥反应，可能反映了直接干扰产生的T细胞效应器功能的局部(胎盘)因素，或者导致这种细胞缺失的未知因素。然而，这些机制显然是可以被打破的。这一建议着眼于更广泛的组织特异性耐受性，并表明尽管怀孕和未怀孕小鼠的幼稚T细胞的激活或失活规则是相同的，但在怀孕宿主中，控制有抗原经历的T细胞的增殖、运输和死亡的动态平衡机制可能是独一无二的。此外，研究还表明，对这些过程的调节呈现出一种可逆的机制(S)，通过该机制，母亲的免疫系统满足保护和耐受胎儿这两个相互竞争的要求。特别是，这项建议试图检查母体T细胞的组织特异性变化，确定这些变化是否与抗原(特别是胎儿/胎盘抗原)特异，并评估先前外源(即怀孕外)暴露于抗原是否会改变这些影响。实验将利用针对H-Y(所有哺乳动物的雄性细胞上表达的抗原)、同种抗原和实验表达的卵清蛋白的T细胞受体(TCR)转基因小鼠。对上述假设的检验可能有助于解释文献中关于母体免疫系统是否受到抑制的相互矛盾的数据。这种测试还可能揭示组织特异性耐受和免疫的新机制，可用于开发治疗复发性流产、自身免疫性疾病和性传播感染的新策略。

DESCRIPTION (provided by applicant): There remain large gaps in our understanding of T cell homeostasis and its role in tissue specific tolerance. This application addresses these issues through the example of maternal immunity to antigens expressed on the fetus and placenta. Maternal tolerance of the fetus is thought to rely on several mechanisms, including limitation of cellular traffic across the maternal-fetal interface and suppression or deletion of fetal antigen specific T cells. However, others and we have shown that cellular traffic can occur between mother and fetus, and that immunity to fetal antigens can be generated during pregnancy. The result of such immunity is typically not one of fetal rejection, perhaps reflecting local (placental) factors that directly interfere with generated T cell effector function, or yet unknown factors that cause deletion of such cells. Nonetheless it is clear that these mechanisms can be broken. This proposal takes a broader view of tissue specific tolerance and suggests that while the rules for activation or inactivation of naive T cells are the same in pregnant and non pregnant mice, the homeostatic mechanisms governing the proliferation, trafficking and death of antigen experienced T cells may be unique in the pregnant host. It moreover suggests that regulation of these processes presents a reversible mechanism(s) by which the maternal immune system meets the two competing requirements of protection and tolerance of the fetus. In particular, this proposal seeks to examine tissue specific changes in maternal T cells, determine if these changes are antigen (particularly fetal/placental antigen) specific, and to evaluate whether prior exogenous (i.e. outside of pregnancy) exposure to antigen alters these effects. The experiments will utilize T cell receptor (TCR) transgenic mice specific for H-Y, (the antigen expressed on male cells of all mammals), allo-antigen, and experimentally expressed ovalbumin. Testing of the stated hypothesis may help explain the literature's conflicting data on whether the maternal immune system is suppressed. Such testing may also reveal novel mechanisms of tissue specific tolerance and immunity that can be used in the development of new strategies to treat recurrent miscarriage, autoimmune disease and sexually transmitted infections.