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            <h1 id="seo-header">实用免疫学（五）适应性免疫：细胞免疫一 Th细胞</h1>
            
            
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                <p>Th0细胞通过表面黏附分子（T细胞表面的LFA-1、ICAM-1、CD2分别和APC的ICAM-1、LFA-1、LFA-3）和DC细胞发生短暂的可逆结合，有利于TCR特异性识别pMHCII（Ag－MHCII复合物）。</p>
<ul>
<li>TCR：有αβ和γδ两种，αβT占95％<br>由成簇的V、D、J基因节段以及恒定的C区基因间断排列而成<br>基因重组酶参与TCR基因片段重排，遵循类似Ig的12／23法则<br>TCRα和TCRβ都是位于T细胞膜上的类Ig结构，两条链通过细胞膜外的半胱氨酸残基形成的二硫键共价联合在一起</li>
<li>12／23法则<br>Ig胚系基因重组时，带有12bp的RSS只能和带有23bp的RSS结合，从而保证基因片段间的正确连接和重排</li>
<li><a target="_blank" rel="noopener" href="https://zhuanlan.zhihu.com/p/225711723">TCR复合物</a><br>包含一个TCRαβ异二聚体，两个CD3γε和CD3δε异二聚体，以及一个通过二硫键相连的ξ同二聚体<br>TCRα和TCRβ都是位于T细胞膜上的类Ig结构，两条链通过细胞膜外的半胱氨酸残基形成的二硫键共价联合在一起（在TCRα和TCRβ链的恒定区后面连接着一小段Hinge结构，Hinge结构中存在半胱氨酸残基，两个半胱氨酸残基形成二硫键把两条链联系在一起）。每一条TCR的链包含一个类似免疫球蛋白的N末端可变区和恒定区，一个疏水的跨膜结构，以及一个非常短的胞内区域。总体来看，TCRαβ胞外区域的结构和抗体的抗原结合域（Fab）非常相似。TCRα和TCRβ链的可变区分别有3个类似于抗体可变区的互补决定区（CDR），这6个CDR共同形成了pMHC在TCR上的结合位点。</li>
</ul>
<p>当Th0的TCR和pMHCII特异性结合后，CD4也随后和MHCII分子β2结构域发生结合，导致CD4在物理上靠近TCR复合物。</p>
<p><img src="https://img-cdn.limour.top/blog/20220222233140.png" srcset="https://jscdn.limour.top/gh/Limour-dev/Sakurairo_Vision/load_svg/inload.svg" lazyload></p>
<ul>
<li>CD4：TCR的共受体，在T细胞的激活过程中起到促进的作用<br>可以结合到MHCII分子上，同时识别pMHCII复合物，增强TCR复合物和DC的结合<br>在结构上CD4是一种跨膜的糖蛋白，属于Ig超家族。有四个细胞外的类Ig结构域，一个疏水的跨膜结构以及38个氨基酸长度的胞内结构域；胞外的两个类Ig结构域可以和MHC-II的α2和β2结合。<br>胞内结构域上附着结合着Src酪氨酸激酶家族的成员——Lck</li>
</ul>
<p>伴随CD4靠近TCR复合物，在细胞内，CD4上的Lck分子和CD3、ξ上的ITAM靠近，随后Lck就将ITAM上的酪氨酸残基磷酸化，ITAM的磷酸化随后导致ZAP-70酪氨酸激酶的募集和活化，ITAM的结构中有两个酪氨酸残基，这两个酪氨酸残基被磷酸化以后可以和ZAP-70结合，结合上去的ZAP-70被Lck磷酸化。ZAP-70被磷酸化后获得它本身的酪氨酸激酶活性并进一步通过磷酸化作用，活化另外两个重要的衔接蛋白LAT和SLP-76，最终通过 Ras–MAP 和PLCγ1信号通路引发T细胞内一系列的下游通路，使得Th0细胞初步活化。</p>
<p>在某些下游通路的刺激下，多个TCR-pMHC向Th0和DC接触面的中央移动。在其中某个下游通路中，有LFA-1构象发生改变，增强ICAM-1的亲和力，从而稳定Th0与DC的结合。此过程最终会形成免疫突触的结构。</p>
<ul>
<li>免疫突触：多个TCR-pMHC&#x2F;CD4&#x2F;CD28在中央，周围围绕着IFA-1-ICAM-1 等共刺激分子的相对密闭的突触状结构<br>增强 T 细胞和 APC 结合的亲和力；引发胞膜分子的一系列变化，促进信号转导、细胞骨架系统和细胞器的变化</li>
</ul>
<p>Th0细胞初步活化的同时，DC也被激活，上调协同刺激分子B7，为Th0细胞进一步活化做准备</p>
<ul>
<li>B7分子：主要包括B7-1（CD80）和B7-2（CD86），主要表达于DC细胞。<br>B7分子与CD28分子结合产生的共刺激信号对Th0细胞的活化起重要作用，一方面通过诱导T细胞分泌抗凋亡蛋白，维持细胞的存活；另一方面刺激T细胞合成分泌重要的生长因子IL-2，促进T细胞的增殖和分化。</li>
<li>CD28：表达于Th0细胞，由两条相同的肽链组成的同源二聚体</li>
<li>IL-2：来自Th1，T细胞自分泌生长因子、B细胞旁分泌生长因子、激活NK细胞形成LAK</li>
<li>LAK：淋巴因子激活的杀伤细胞，对肿瘤细胞具有特异的细胞毒性（可以裂解NK不能裂解的细胞）</li>
</ul>
<p>当CD28和DC表面的B7结合后，初步活化的Th0细胞开始分泌关键的IL-2，从G0期进入G1期，完成最后的激活。并在其他细胞因子的作用下，决定分化的方向：</p>
<ul>
<li><p>Th1：分化主要由细胞因子IL-12和IFN-y诱导；主要通过分泌IL-2、IFN-γ，增强巨噬细胞的功能，介导抗胞内病原体的细胞免疫。参与慢性炎症和自身免疫疾病。</p>
</li>
<li><p>IL-12：来自DC；【早期】激活NK细胞分泌IFN-γ；【晚期】诱导Th1分化</p>
</li>
<li><p>IFN-γ：来自NK细胞、Th1；激活巨噬细胞；促进Th1分化，抑制Th2分化</p>
</li>
<li><p>Th2：分化主要由细胞因子IL-4诱导；主要通过分泌IL-4、IL-5、IL-13，促进B细胞分泌IgE、肥大细胞嗜酸性细胞嗜碱性细胞活化、介导抗寄生虫感染。参与过敏。</p>
</li>
<li><p>IL-4：来自Th2；刺激B细胞增殖、肥大细胞发育、IgE生成</p>
</li>
<li><p>IL-5：来自Th2；促进嗜酸性细胞生长、IgA生成</p>
</li>
<li><p>IL-13：来自Th2、CD4T、NKT、Mast、Baso、eosino、nuo，促进IgE生成、杯状细胞增生和分泌黏液，与过敏相关。</p>
</li>
<li><p>Th17：分化主要由TGF-β、IL-6诱导，主要分泌IL-17（A和F）和IL-22，促进中性粒细胞的招募和活化，介导多种急性和慢性组织炎症。参与自身免性疾病。</p>
</li>
<li><p>TGF-β：来自成纤维细胞；抗病毒作用、促进MHC分子表达</p>
</li>
<li><p>IL-6：来自巨噬细胞；诱导CRP合成、内生致热原</p>
</li>
<li><p>IL-17：来自Th17， 通常被称为 CTLA8，趋化因子</p>
</li>
<li><p>IL-22：来自Th1、Th2、Th17、γδT、NKT、ILC3、neutro、macro，作用于非造血细胞，刺激细胞存活、增殖和抗菌剂的合成，参与伤口愈合和抗感染</p>
</li>
<li><p>ILC3：来自淋巴谱系的免疫细胞，参与粘膜的先天机制，有助于组织稳态、宿主共生共生和病原体清除。</p>
</li>
</ul>
<p><img src="https://img-cdn.limour.top/blog/20220223004935.png" srcset="https://jscdn.limour.top/gh/Limour-dev/Sakurairo_Vision/load_svg/inload.svg" lazyload></p>
<p>Th细胞迁移到外周组织、遇到抗原并发生二次活化（仅CD3、ξ活化信号即可），从而发挥其具体的效应。</p>
<p>Th细胞迁移至感染部位与归巢表型相关</p>
<ul>
<li>Th1：选择素配体、CXCR3、CCR5</li>
<li>Th2：CCR3、CCR4、CCR8</li>
<li>Th17：CCR6</li>
</ul>
<h2 id="Th1细胞的效应"><a href="#Th1细胞的效应" class="headerlink" title="Th1细胞的效应"></a>Th1细胞的效应</h2><p>Th细胞本身并不直接杀伤和清除病原体，而是通过分泌细胞因子和表达细胞表面分子，活化其他免疫细胞，增强其效应功能，从而清除病原体。</p>
<ul>
<li><p>通过分泌细胞因子，介导中性粒细胞、单核细胞和嗜酸性粒细胞到达感染部位</p>
</li>
<li><p>通过分泌细胞因子和表达CD40L两种主要机制活化白细胞</p>
</li>
<li><p>诱导并募集巨噬细胞：Th1细胞产生IL－3和GM－CSF，促进骨髓造血干细胞分化为单核细胞；产生TNF－α、LTα和CCL2，诱导炎症部位血管内皮细胞高表达黏附分子，促进单核细胞和淋巴细胞的血管内皮黏附，继而穿越血管壁趋化到局部组织</p>
</li>
<li><p>激活巨噬细胞：Th1产生IFNγ，表达CD40L与巨噬细胞表面的CD40结合，导致转录因子NF－κB和AP－1的激活，促进巨噬细胞的吞噬溶酶体表达多种蛋白酶和溶解酶，诱导ROS和iNOS产生，后者可刺激一氧化氮的合成，最终杀伤巨噬细胞吞噬的微生物。IFNγ、CD40L激活的M1型巨噬细胞具有强大的杀菌能力，同时也通过高表达B7和MHCII类分子，从而具有更强的呈递抗原和活化CD4＋T细胞的能力，分泌的 IL12、IL1、TNF等细胞因子，可促进Th1细胞分化，并进一步招募白细胞到达感染组织</p>
</li>
<li><p>当病原体能有效抵抗活化巨噬细胞的杀菌作用时，会发生慢性感染炎症，例如慢性结核分歧杆菌感染的特征性标志肉芽肿就是Th1细胞活化巨噬细胞引起的组织病理改变</p>
</li>
<li><p>而当CD4＋T细胞缺失时，不能有效激活巨噬细胞，如HIV感染的患者常死于卡氏肺囊虫感染引发的肺炎，而M1型巨噬细胞能吞噬并杀伤清除卡氏肺囊虫</p>
</li>
<li><p>Th1产生的LT和TNFα可活化中性粒细胞，促进其杀伤病原体。但活化的巨噬细胞和中性粒细胞分泌的杀菌分子，不区分微生物和宿主组织，可造成正常组织的损伤。不过感染清除后可以通过组织修复而恢复</p>
</li>
<li><p>Th1产生IFNγ作用与B细胞，促进抗体类型转化为IgG，且抑制IL4依赖的IgE类型转化</p>
</li>
<li><p>产生的IF2可促进CTL分化，激活的M1高表达的B7分子可作为第二信号活化CTL细胞</p>
</li>
</ul>

                
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