The Immunobiology Vaccine Center, The Department of Microbiology, The University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
PLoS One. 2011;6(11):e27501. doi: 10.1371/journal.pone.0027501. Epub 2011 Nov 7.
Our previous studies have shown that Peyer's patches (PPs) play a key role in the induction of oral tolerance. Therefore, we hypothesized that PPs are an important site for Transforming Growth Factor (TGF)-β signaling and sought to prove that this tissue is of importance in oral tolerance induction. We found that expression of TGF-β type II receptor (TGFβRII) by CD4(+) T cells increases and persists in the PPs of normal C57BL/6 mice after either high- or low-dose feeding of OVA when compared to mesenteric lymph nodes (MLNs) and spleen. Approximately one-third of these TGFβRII(+) CD4(+) T cells express the transcription factor Foxp3. Interestingly, the number of TGFβRII(+) CD4(+) T cells in PPs decreased when OVA-fed mice were orally challenged with OVA plus native cholera toxin (CT). In contrast, numbers of TGFβRII(+) CD4(+) T cells were increased in the intestinal lamina propria (iLP) of these challenged mice. Further, these PP CD4(+) TGFβRII(+) T cells upregulated Foxp3 within 2 hours after OVA plus CT challenge. Mice fed PBS and challenged with OVA plus CT did not reveal any changes in TGFβRII expression by CD4(+) T cells. In order to test the functional property of TGFβRII in the induction of oral tolerance, CD4dnTGFβRII transgenic mice, in which TGFβRII signaling is abrogated from all CD4(+) T cells, were employed. Importantly, these mice could not develop oral tolerance to OVA. Our studies show a critical, dose-independent, role for TGFβRII expression and function by CD4(+) T cells in the gut-associated lymphoid tissues, further underlining the vital role of PPs in oral tolerance.
我们之前的研究表明，派尔氏斑（PPs）在诱导口服耐受中起关键作用。因此，我们假设 PPs 是转化生长因子（TGF）-β信号的重要部位，并试图证明该组织在口服耐受诱导中很重要。我们发现，与肠系膜淋巴结（MLN）和脾脏相比，高剂量或低剂量喂食 OVA 后，正常 C57BL/6 小鼠的 PPs 中 CD4+T 细胞的 TGF-β Ⅱ型受体（TGFβRII）表达增加并持续存在。这些 TGFβRII+CD4+T 细胞中约有三分之一表达转录因子 Foxp3。有趣的是，当喂食 OVA 的小鼠用 OVA 加天然霍乱毒素（CT）进行口服挑战时，PP 中的 TGFβRII+CD4+T 细胞数量减少。相比之下，在这些受挑战的小鼠的肠固有层（iLP）中，TGFβRII+CD4+T 细胞的数量增加。此外，这些 PP CD4+TGFβRII+T 细胞在接受 OVA 加 CT 挑战后 2 小时内上调了 Foxp3。用 PBS 喂食并用 OVA 加 CT 挑战的小鼠，CD4+T 细胞的 TGFβRII 表达没有任何变化。为了测试 TGFβRII 在诱导口服耐受中的功能特性，我们使用了 CD4dnTGFβRII 转基因小鼠，在该小鼠中，所有 CD4+T 细胞的 TGFβRII 信号均被阻断。重要的是，这些小鼠不能对 OVA 产生口服耐受。我们的研究表明，TGFβRII 表达和功能在肠道相关淋巴组织中的 CD4+T 细胞中起着关键的、剂量独立的作用，进一步强调了 PPs 在口服耐受中的重要作用。
