THE T-CELL RESPONSE TO ANTIGEN

一种可能在这些反应中发挥早期和关键作用的基因产物是我们克隆的一种T细胞细胞因子，称为Eta-1(用于早期T淋巴细胞激活-1)。该基因具有以下特点：Eta-1基因是TCR连接后表达的最丰富的新转录的mRNA物种，编码一种分泌型磷酸蛋白，在体内外导致巨噬细胞活化和趋化迁移，可能是导致对多种细胞内病原体的遗传抗性的原因。Eta-1的过度表达可能在MRL/LPR小鼠自身免疫性疾病的发病机制中起核心作用。我们最近的研究表明，靶基因突变继发于Eta-1基因表达缺陷的小鼠在病毒感染后不能产生DTH反应和相关的Th1驱动的自身免疫。这些缺陷的免疫反应与体内IL-12的产生减少和IL-10的过度产生有关。这种体内反应可能反映了Eta-1的N端部分与其整合素受体Alphavbeta3之间的相互作用，导致IL-12的分泌和IL-10的表达被抑制。这些发现确认Eta-1是一种关键的、非冗余的细胞因子，可以启动Th1炎症反应，并提供了一种机制，通过这种机制，T细胞对外来抗原的识别可以控制抗微生物炎症反应的发展。我们建议进行结构/功能研究，以确定ETA-1与巨噬细胞受体(S)(SA1)之间的分子相互作用以及随后调节IL-12/IL-10基因表达的细胞内事件(SA2)。我们还建议进行研究，以确定Eta-1在Th1/DTH对常规抗原(SA3)的发展中的作用，以及它在Th1依赖的微生物病原体和器官特异性自身免疫病(SA4)反应中的作用。

A gene product that may play an early and critical role in these responses is a T-cell cytokine we have cloned termed Eta-1 (for Early T-lymphocyte activation-1). This gene has the following features: the Eta-1 gene is the most abundant newly-transcribed mRNA species expressed after TCR ligation, encoding a secreted phosphoprotein that leads to macrophage activation and chemotactic migration in vitro and in vivo and may account for genetic resistance to several intracellular pathogens. Overexpression of Eta-1 may play a central role in the pathogenesis of autoimmune disease in MRL/lpr mice. Our recent studies indicate that mice deficient in Eta-1 gene expression secondary to targeted gene mutation fail to develop DTH responses and associated Th1-driven autoimmunity after viral infection. These defective immune responses are associated with diminished in vivo production of IL-12 and excessive production of IL-10. This in vivo response may reflect an interaction between the N- terminal portion of Eta-1 and its integrin receptor, alphavbeta3, leading to IL-12 secretion and inhibition of IL-10 expression. These findings identify Eta-1 as a critical and non-redundant cytokine that initiates Th1 inflammatory responses and provide a mechanism by which T-cell recognition of foreign antigens may govern the development of antimicrobial inflammatory responses. We propose structure/function studies to define the molecular interaction between Eta-1 and macrophage receptor(s) (SA1) and subsequent intracellular events (SA2) that regulate IL-12/IL-10 gene expression. We also propose studies to define the role of Eta-1 in Th1/DTH development to conventional antigen (SA3) and its contribution to Th1-dependent responses to microbiological pathogens and organ-specific autoimmune disease (SA4).