Mechanisms of reduced T cell autoimmunity with immune experience

卫生假说指出，接触微生物和 自身免疫的发展，即你的环境越“干净”，自身免疫的可能性就越高 发展。造成这种情况的原因尚不清楚。因此，我们对卫生知识的了解存在着明显的空白 假说，包括微生物暴露后宿主发生了什么变化，以及这如何影响自身特异性 免疫力导致自身免疫力下降。我们已经复制了卫生假说的各个方面，使用 易于处理的、抗原特异性的小鼠感染和自身免疫模型。我们的数据显示，之前的归纳 不同条件性环境(感染或与自身抗原相互作用)驱动下的T细胞免疫 几个月后，自身特异性CD8 T细胞的激活减少。无能OTI T细胞的存在将减少未来 自身免疫病理，自身特异的CD8T细胞的增殖和功能都被钝化。我们观察到 在LCMV免疫小鼠和“脏”小鼠中也有相同的结果。以前的免疫经验与更早的 在应答自身特异性CD8T细胞时诱导耐受性签名。这是自身抗原所特有的，因为 外来抗原特异性T细胞反应不受影响。这些目标将检验以前的T 细胞反应改变淋巴组织中自身抗原的产生和/或提呈，以加速耐受诱导。 目标1将确定淋巴结中间质细胞的变化是否与自身特异性CD8降低有关 免疫经验小鼠的T细胞活化。IFABP-OVA小鼠60h后OTI细胞分裂减少 在免疫经验宿主的腹股沟LN中，这是由非迁移细胞驱动的。由于LN中的间质细胞可以 产生组织限制性抗原，这些细胞的变化可能会对自身特异的CD8T细胞产生负面影响 激活。我们将评估LN基质细胞的数量、表观遗传学和表型特征。 对于观察到的变化，免疫经验丰富的小鼠和检测I型干扰素、干扰素、IL-6或肿瘤坏死因子是重要的。 目标2将确定LN间质细胞上自身抗原提呈增加是否导致减少 自身免疫力。我们还将评估组织限制性抗原在免疫经验丰富的动物中的表达。 作为其陈述的重要因素，如EIRE和DEAF1。这些内容的表达将在 结合KB-SIINFEKL复合体的染色，以及活体小鼠T细胞的体内成像。总的来说， 这一应用将确定改变自身抗原产生或呈递的新机制。 由于以前的环境规划来自适应性免疫反应。它还解决了 重要的，但机械上尚未解决的卫生假说，一个与TCR交叉的基本主题 反应性与环境影响，导致耐受或自身免疫的结果截然不同。

The hygiene hypothesis states that there is an inverse correlation between exposure to microbes and the development of autoimmunity, i.e., the “cleaner” your environment is, the higher probability autoimmunity will develop. The reason for this is unclear. Thus, there are outstanding gaps in our knowledge about the hygiene hypothesis, including what changes occur in the host after microbial exposure and how this affects self-specific immunity leading to decreased autoimmunity. We have replicated aspects of the hygiene hypothesis using tractable, antigen-specific mouse models of infection and autoimmunity. Our data show that previous induction of T cell immunity under different conditioning contexts (infection or interaction with self-antigen) drives decreased self-specific CD8 T cell activation months later. The presence of anergic OTI T cells decreases future autoimmune pathology, as both the proliferation and function of self-specific CD8 T cells is blunted. We observe the same outcome in LCMV immune mice and in `dirty' mice. Previous immune experience is linked to earlier induction of a tolerant signature in responding self-specific CD8 T cells. This is specific for self-antigen, as foreign-antigen-specific T cell responses are unaffected. These aims will test the hypothesis that previous T cell responses alter self-antigen production and/or presentation in lymphoid tissue to speed tolerance induction. Aim 1 will determine whether changes in stromal cells in lymph nodes contribute to decreased self-specific CD8 T cell activation in immune-experienced mice. OTI cell division in iFABP-ova mice is reduced 60h post priming in inguinal LN of immune-experienced hosts, which is driven by non-migratory cells. As stromal cells in LN can produce tissue-restricted antigens, changes in these cells may negatively affect self-specific CD8 T cell activation. We will evaluate the number, epigenetic and phenotypic signature of LN stromal cells in naïve and immune-experienced mice and test if type I IFN, IFN, IL-6 or TNF, are important for the observed changes. Aim 2 will establish whether increased self-antigen presentation on LN stromal cells is responsible for decreased autoimmunity. We will evaluate expression of tissue-restricted antigens in immune-experienced animals, as well as factors important for their presentation, such as AIRE and DEAF1. Expression of these will be quantified in conjunction with staining for Kb-SIINFEKL complexes, as well as in vivo imaging of T cells in live mice. Overall, this application will determine the novel mechanisms by which self-antigen production or presentation is altered due to previous environmental programming from the adaptive immune response. It also addresses the important, but mechanistically unresolved, hygiene hypothesis, a fundamental topic intersecting TCR responsiveness with environmental impact, leading to vastly different outcomes of tolerance or autoimmunity.