Characterizing MHCI's neuroactivity

描述(申请人提供)：主要组织相容性I类(MHCI)已被广泛研究，因为它在CD8+T细胞的阳性和阴性选择中的作用，以及在激活或抑制T细胞和NK细胞中的作用。除了对炎性细胞因子、创伤或功能损伤的反应外，神经元被认为很少或根本不表达MHCI。然而，最近的研究表明，MHCI是由一些神经元表达的，这些神经元的突触经历了活性依赖性的重塑。值得注意的是，缺乏82M、TAP1和CD3的小鼠在消除不适当的神经元突触连接方面存在缺陷，这表明MHCI和包含CD3^的受体参与了神经元突触连接的选择。因此，参与免疫系统功能的关键分子也可能参与中枢神经系统的发育和可塑性。虽然功能性MHCI的缺乏与发育中的中枢神经系统异常有关，但MHCI的神经活性尚未被直接检测。我们在这里描述的体外外植体系统是第一个对外源性MHCI有反应的神经元模型。我们的结果表明，MHCI在体外可以抑制神经元的生长。这种MHCI神经活性与其在选择突触连接中的作用不同，可能与MHCI抑制T细胞和NK细胞功能的能力相似。使用这个体外系统，我们可以解决这个新兴领域的几个关键问题。首先，中枢神经系统受体对MHCI的识别是否依赖于特定的MHCI等位基因和递呈多肽(就像在适应性免疫系统中一样)，或者它对MHCI等位基因和递呈多肽的识别是否是非特异性的(就像在天然免疫系统中经常发生的那样)。第二，虽然关于MHCI在中枢神经系统中的表达模式的信息越来越多，但对MHCI受体(S)在中枢神经系统中的表达模式知之甚少。使用MHCI受体配体，我们将首次在中枢神经系统组织切片中可视化经典的MHCI受体。我们将描述MHCI受体在发育中的中枢神经系统中的表达模式。最后，我们将确定不同的MHCI蛋白/肽组合是否被不同的神经元识别。这项R21提案解决了一个新研究领域的关键问题，其结果可能提供重要的概念进步。可以想象，限制MHCI神经抑制作用的治疗可能会带来减轻神经病理障碍的新的临床方法。

DESCRIPTION (provided by applicant): Major histocompatibility class I (MHCI) has been widely studied because of its role in the positive and negative selection of CD8+ T cells, and in activating or suppressing T cell and NK cells. Neurons have been thought to express little or no MHCI, except in response to inflammatory cytokines, trauma, or functional impairment. However, recent studies have demonstrated that MHCI is expressed by some neurons whose synapses undergo activity-dependent remodeling. Notably, mice lacking 82M, TAP1 and CD3¿ have deficiencies in eliminating inappropriate neuronal synaptic connections, suggesting that MHCI and a CD3^-containing receptor are involved in the selection of neuronal synaptic connections. Thus, key molecules involved in immune system function may also be involved in CNS development and plasticity. Although the lack of functional MHCI has been associated with developmental CNS aberrations, the neuroactivity of MHCI has not been directly tested. The in vitro explant system we describe herein is the first neuronal model to be responsive to exogenous MHCI. Our results show that MHCI can inhibit neuronal outgrowth in vitro. This MHCI neuroactivity is distinct from its proposed role in selecting synaptic connections, and may have parallels with MHCI's ability to inhibit T cell and NK cell function. Using this in vitro system, we can address several of the key questions in this emerging field. First, does the recognition of MHCI by CNS receptors depend on the specific MHCI allele and the presented peptide (as in the adaptive immune system), or is its recognition non-specific for the MHCI allele and presented peptide (as often occurs in the innate immune system). Second, while there is growing information on the expression pattern of MHCI in the CNS, little is known about the expression pattern of MHCI receptor(s) in the CNS. Using MHCI receptor ligands, we will for the first time, visualize classical MHCI receptors in CNS tissue sections. We will characterize the expression pattern of MHCI receptors in the developing CNS. Finally, we will determine whether different MHCI alelle/peptide combinations are recognized by different neurons. This R21 proposal addresses key questions in a new area of research, the results of which may provide important conceptual advances. Conceivably, treatments that limit the neuroinhibitory effects of MHCI could lead to new clinical approaches to mitigate neuropathological disorders.