In vivo significance of T-reg cells during FIV infection

描述（由申请人提供）：我们描述了猫体内的CD4+CD25+ Treg细胞，并证明它们在猫免疫缺陷病毒（FIV）感染的动物体内被慢性激活。FIV感染猫的Treg细胞明显抑制CD4+CD25- T细胞的增殖，并且由于慢性FIV感染，Treg细胞在体内明显被激活。由于活化的Treg细胞在抑制功能上是非抗原特异性的，因此这些细胞可能反过来抑制或抑制CD4+ T辅助反应，包括FIV抗原，从而导致这种感染的获得性免疫缺陷综合征（AIDS）。最近在HIV-1感染者中也报道了同样的观察结果，有趣的是，Treg功能水平的增加与良好的临床状态或对HAART的反应有关。正常情况下，Treg的功能对于限制和下调免疫反应，防止过度炎症和自身免疫性疾病至关重要。HIV感染中的Treg细胞是有益还是有害尚不清楚，答案可能取决于疾病的阶段。在急性感染期间，hiv诱导的Treg活性可能会限制抗病毒反应的范围和效力，而在无症状感染期间，Treg活性可能有助于控制慢性免疫激活并限制活化靶细胞的可用性。解决Treg功能在HIV感染过程中的重要性的最明确方法是在动物模型中耗尽Treg细胞。在这些研究中，我们将采用HIV的FIV/cat模型：2.确定在FIV感染之前或之后立即消耗Treg细胞是否会导致更有效的抗病毒免疫反应。确定FIV感染无症状期Treg细胞的消耗是否会导致抗病毒t细胞免疫扩增和/或血浆病毒血症的改变。这些研究的结果将提供对Treg在HIV感染中的功能的临床理解，并将指导未来调节Treg功能的方法。

DESCRIPTION (provided by applicant): We have described CD4+CD25+ Treg cells in the cat and demonstrated that they are chronically activated in feline immunodeficiency virus (FIV) infected animals. Treg cells from FIV-infected cats significantly inhibited proliferation of CD4+CD25- T cells, and are apparently activated in vivo as a result of the chronic FIV infection. As activated Treg cells are non-antigen specific in their suppressive function, it is possible that these cells could in turn suppress or anergize CD4+ T helper responses to a variety of antigens including FIV antigen and thereby contribute to the acquired immunodeficiency syndrome (AIDS) characteristic of this infection. The same observation has recently been reported in HIV-1 infected people and interestingly, increased levels of Treg function were associated with a favorable clinical status or respose to HAART. Normally, Treg function is critical to limit and down-regulate immune responses, preventing excessive inflammation and autoimmune disease. Whether Treg cells in HIV infection are beneficial or detrimental is unclear and the answer may depend on the stage of disease. It is possible that HIV-induced Treg activity during acute infection may limit the scope and efficacy of the anti-viral response, whereas Treg activity during asymptomatic infection may serve to control chronic immune activation and limit availability of activated target cells. The most definitive way to address the significance of Treg function during HIV infection is to deplete Treg cells in an animal model. In these studies we will employ the FIV/cat model of HIV to: 1.) Determine whether depletion of Treg cells before or immediately after FIV infection results in a more effective anti-viral immune response, and 2.) Determine whether depletion of Treg cells during the asymptomatic phase of FIV infection results in the expansion of antiviral T-cell immunity and/or change in plasma viremia. Results from these studies will provide a clinical understanding of Treg function in HIV infection and will guide future approaches to modulate Treg function.