Program of Developmental Immunology, Department of Pediatrics, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02114, USA.
Gastroenterology. 2011 Nov;141(5):1813-20. doi: 10.1053/j.gastro.2011.06.076. Epub 2011 Jul 13.
BACKGROUND & AIMS: Immune responses in the intestine are controlled by regulatory T cells (Tregs), which prevent inflammation in response to commensal bacteria. A specific population of intestinal dendritic cells (DCs), marked by expression of CD103, generate Tregs more efficiently than other DC populations through mechanisms that involve retinoic acid and transforming growth factor (TGF)-β. However, it is not clear how CD103(+) DCs are specialized for this function. We investigated the ability of CD103(+) DCs to promote Treg generation through activation of TGF-β and the role of integrins with the αv subunit in this process.
Naïve T cells were cultured with purified DCs from mesenteric lymph nodes (MLNs) or intestines of wild-type and αv conditional knockout mice to assess generation of Tregs. Antigens were administered orally to mice, and antigen-specific generation of Tregs was measured in intestinal tissues. Expression of the integrin αv subunit was measured in purified subpopulations of DCs by quantitative polymerase chain reaction and immunoblot analyses.
In vitro, CD103(+) DCs generated more Tregs in the presence of latent TGF-β than other MLN DCs. Efficient generation of Tregs required expression of the integrin αv subunit by DCs; mice that lacked αv in immune cells did not convert naïve T cells to intestinal Tregs in response to oral antigen. CD103(+) DCs derived from the MLNs selectively expressed high levels of integrin αvβ8 compared with other populations of DCs.
Expression of αvβ8 is required for CD103(+) DCs to become specialized and activate latent TGF-β and generate Tregs during the induction of tolerance to intestinal antigens in mice.
肠道中的免疫反应受调节性 T 细胞（Tregs）控制，Tregs 可防止对共生细菌的炎症反应。一类表达 CD103 的肠道树突状细胞（DCs）通过涉及视黄酸和转化生长因子（TGF）-β的机制，比其他 DC 群体更有效地产生 Tregs。然而，CD103(+) DCs 如何专门发挥此功能尚不清楚。我们研究了 CD103(+) DC 通过激活 TGF-β促进 Treg 产生的能力，以及整合素 αv 亚基在该过程中的作用。
用来自肠系膜淋巴结（MLN）或野生型和 αv 条件性敲除小鼠肠道的纯化 DC 培养原代 T 细胞，以评估 Treg 的产生。将抗原经口给予小鼠，测量肠道组织中抗原特异性 Treg 的产生。通过定量聚合酶链反应和免疫印迹分析测量纯化的 DC 亚群中整合素 αv 亚基的表达。
体外，与其他 MLN DC 相比，CD103(+) DC 在潜伏 TGF-β存在的情况下生成更多的 Treg。Treg 的有效产生需要 DC 表达整合素 αv 亚基；缺乏免疫细胞中 αv 的小鼠在口服抗原后不能将原代 T 细胞转化为肠道 Treg。与其他 DC 群体相比，MLN 衍生的 CD103(+) DC 选择性地高表达整合素 αvβ8。
在诱导小鼠对肠道抗原产生耐受的过程中，αvβ8 的表达是 CD103(+) DC 变得特化并激活潜伏 TGF-β和产生 Treg 所必需的。
