Regulation of Gender Dependent EAE Susceptibility

描述（由申请人提供）：本申请探讨了CD25+ T细胞和NK1.1+细胞在性别和年龄依赖的自身免疫性疾病抵抗/易感性模型中对APC活性的稳态调节，该模型使用SJL小鼠进行Th1介导的CNS自身免疫性疾病。诱导实验性自身免疫性脑脊髓炎（EAE）的致脑性Th1细胞在所有年龄的女性和成熟男性（bb0 - 12周龄）中都被激活。相比之下，Ag特异性Th2细胞在年轻成年（6周大）雄性中被激活，导致EAE抵抗。抵抗性男性体内CD4 + CD25+T细胞的消耗，而不是年龄匹配的女性，将证明CD25+T细胞抑制Th1激活。过继性转移将证明来自6周耐药雄性的CD25 + T细胞抑制雌性和成熟雄性受体的EAE。我们的假设是，APC在体内改变CD4 + CD25 + T细胞，我们将通过在6周的男性APC受体中诱导EAE来验证。APC受体来自CD25 +缺失的6周男性供者。在EAE抗性雄性中，无论是NK1.1 +细胞的缺失，还是来自NK1.1抗性供体的APC转移，都能诱导Th1反应。通过阻断或受体配体和DAP - 12 KO小鼠的分析，验证了抗性雄性NK细胞频率增加通过细胞间相互作用改变APC的假设。通过体内和体外方法研究了CD25 + T细胞、NK细胞和APC之间通过Th2活化导致EAE耐药的三方相互作用。在NK或CD25 + T细胞耗尽后，将分析每种细胞类型对其他两种细胞类型的细胞因子分泌、表面和基因表达的影响。这些实验将提供一个由性别和年龄调节的单一固定基因型内细胞-细胞相互作用的机制分析，最终影响对自身免疫性疾病的抵抗力或易感性。这些数据也将首次证明NK和CD25 + T细胞通过改变APC功能在抗原遭遇之前影响适应性免疫。

DESCRIPTION (provided by applicant): This application explores the homeostatic regulation of APC activity by CD25+ T cells and NK1.1+ cells in a gender and age dependent autoimmune disease resistance/susceptibility model using SJL mice in a Th1 mediated CNS autoimmune disease. Encephalitogenic Th1 cells inducing experimental autoimmune encephalomyelitis (EAE) are activated in females of all ages and mature males (>12 wks old). By contrast, Ag specific Th2 cells are activated in young adult (6 wk old) males, resulting in EAE resistance. Depletion of CD4 + CD25 + T cells from resistant males, but not age matched females, will demonstrate that CD25+T cells suppress Th1 activation. Adoptive transfers will demonstrate that CD25 + T cells from resistant 6 wk males inhibits EAE in female and mature male recipients. Our hypothesis, that the APC alters the CD4 + CD25 + T cells in vivo will be tested by inducing EAE in resistant 6 wk male recipients of APC derived from CD25 + depleted 6 wk male donors. Th1 responses are also induced in EAE resistant males either depleted of NK1.1 + cells or following APC transfer from NK1.1 depleted resistant donors. The hypothesis that the increased frequency of NK cells in resistant males alters the APC via cell-cell interaction is examined by blockade or receptor ligand and analysis of DAP 12 KO mice. Tripartite interactions between CD25 + T cells, NK cells and APC which lead to EAE resistance via Th2 activation are examined by in vivo and in vitro approaches. The influence of each cell type on cytokine secretion, surface and gene expression in the other two cell types will be analyzed following depletion of either the NK or CD25 + T cells. These experiments will provide a mechanistic analysis of cell-cell interactions within a single fixed genotype regulated by both gender and age which ultimately influence resistance or susceptibility to autoimmune disease. These data will also provide the first evidence that NK and CD25 + T cells influence adaptive immunity prior to antigen encounter via alterations in APC function.