Transient local depletion of Foxp3+ regulatory T cells during recovery from colitis via Fas/Fas ligand-induced death
Transient local depletion of Foxp3+ regulatory T cells during recovery from colitis via Fas/Fas ligand-induced death
复制标题
DOI：
10.4049/jimmunol.180.12.8316
复制
发表时间：
2008-06-15
影响因子：
4.4
通讯作者：
McKay, Derek M.
中科院分区：
文献类型：
--
作者：
Reardon, Colin;Wang, Arthur;McKay, Derek M.
调节性T细胞（T-T细胞）在调节健康和疾病的免疫系统中发挥着重要作用。有相当多的证据表明，转移TGFAP可以治愈结肠炎和各种其他炎症性疾病。然而，很少有人知道炎症对居民T细胞的影响。用半抗原化剂2，4-二硝基苯磺酸（DNBS）直肠内滴注处理的小鼠（BALB/c或C57 BL/6）发生急性炎性疾病，其组织病理学在处理后3天达到峰值，此后自发消退。在这项研究中，我们证明DNBS（或恶唑酮）诱导的结肠炎导致结肠Foxp 3（+）T-lymphocytes的耗竭，而Foxp 3（+）细胞在回肠，肠系膜淋巴结和脾脏中的比例保持不变。结肠T-g群体的补充与粘膜归巢（α（4）β（+）（7））CD 4（+）Foxp 3（+）T-g的重新出现有关。评估局部T-reg耗竭的机制，我们发现没有证据表明Foxp 3（+）群体中马槟榔诱导的表型转换或SMAD 7表达增加，尽管TGF-β在Foxp 3（+）T-reg生物学中具有重要作用。在结肠炎小鼠结肠中观察到Fas配体（FasL）表达增加，并且用Fas交联Ab体外刺激导致CD 4（+）Foxp 3（+）细胞凋亡，但不导致CD 4（+）Foxp 3（-）细胞凋亡。此外，在Fas/FasL缺陷小鼠中，DNBS诱导的结肠炎不会导致结肠T-T细胞耗竭。最后，在DNBS处理后8天，过继转移的协同Fas（-/-）而非Fas（+/+）T-fos在结肠中被保护免于耗尽，从而证实了炎症诱导的小鼠结肠中Foxp 3（+）T-fos的局部耗尽通过Fas/FasL介导的死亡发生的假设。
Regulatory T cells (T-regs) play a fundamental role in regulating the immune system in health and disease. Considerable evidence exists demonstrating that transfer of Tregs can cure colitis and a variety of other inflammatory disorders. However, little is known about the effects of inflammation on resident T-regs. Mice (BALB/c or C57BL/6) treated with an intrarectal instillation of the haptenizing agent 2,4-dinitrobenzene sulfonic acid (DNBS) develop an acute inflammatory disease, the histopathology of which peaks at 3 days posttreatment and resolves spontaneously thereafter. In this study we demonstrate that DNBS (or oxazolone)induced colitis causes a depletion of colonic Foxp3(+) T-regs 8 days posttreatment, while the proportion of Foxp3(+) cells in the ileum, mesenteric lymph nodes, and spleen remains unchanged. Replenishment of the colonic T-g population was associated with the reappearance of mucosal homing (alpha(4)beta(+)(7)) CD4(+)Foxp3(+) T-regs. Assessing the mechanism of local T-reg depletion, we found no evidence to implicate cytokine-induced phenotypic switching in the Foxp3(+) population or increased SMAD7 expression despite the essential role that TGF-beta has in Foxp3(+) T-reg biology. Increased Fas ligand (FasL) expression was observed in the colon of colitic mice and in vitro stimulation with a Fas cross-linking Ab resulted in apoptosis of CD4(+)Foxp3(+) but not CD4(+)Foxp3(-) cells. Furthermore, DNBS-induced colitis in Fas/FasL-deficient mice did not result in depletion of colonic T-regs. Finally, adoptively transferred synergic Fas(-/-) but not Fas(+/+) T-regs were protected from depletion in the colon 8 days post-DNBS treatment, thus substantiating the hypothesis that inflammation-induced local depletion of Foxp3(+) T-regs in the colon of mice occurs via Fas/FasL-mediated death.