修回日期: 2008-02-26
接受日期: 2008-03-05
在线出版日期: 2008-03-18
Foxp3+调节性T细胞在调控免疫病理、防止机体遭受免疫损伤中起到重要作用. 在肠道, 初始T细胞受到抗原激活后表达Foxp3, 这一过程需要维甲酸和转移生长因子(TGF-β)的参与. 维甲酸是肠道相关树突状细胞产生的维生素A的代谢产物, 通过诱导T细胞产生整合素α4β7和CCR9, 提高外周天然T细胞转化为调节性T细胞的能力, 并使其定居肠道. 此外维甲酸还可以减少RORγt, 来降低Th17、提高调节性T细胞的转化.
引文著录: 郑丽坤, 张磊, 陈乃耀. 维甲酸和肠道免疫稳态. 世界华人消化杂志 2008; 16(8): 885-891
Revised: February 26, 2008
Accepted: March 5, 2008
Published online: March 18, 2008
FOXP3+ regulatory T cells play a key role in controlling immune pathological reactions and preventing organs from immune damages. In the gut, native T cells express FOXP3 when antigens make T cells active. It is necessary for the retinoic acid and transforming growth factor β(TGF-β) to involve in the procession. The retinoic acid is the metabolite of vitamin A produced by gut-associated dendritic cells, with induction T cells to produce integrin α4β7 and CCR9, which enhance the ability in transferring native T cells into regulatory T cells, and regulatory T cells migrate preferentially to the small intestine. Besides, retinoic acid can make RORγt weak, resulting in the reduction of Th17 and the improvement of regulatory T cell transformation.
- Citation: Zheng LK, Zhang L, Chen NY. Role of retinoic acid in gut immune homeostasis. Shijie Huaren Xiaohua Zazhi 2008; 16(8): 885-891
- URL: https://www.wjgnet.com/1009-3079/full/v16/i8/885.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v16.i8.885
为了维持体内的免疫稳态, 小肠的免疫系统已经进化并具备了足够抗炎免疫调节机能: 对无毒害食物和肠道中的共栖微生物发生耐受, 避免机体发生自身免疫性疾病和超敏反应; 同时肠道的免疫系统还会识别并清除局部入侵的致病原, 以避免机体受损. 肠道免疫的建立和维护, 调节性T细胞(regulatory T cells, Treg)发挥着不可或缺的作用. 肠道是大量Treg的定居场所, 包括Foxp3+的Treg. 这些Treg大多来自于胸腺, 但也可来自外周天然T细胞. 肠道微环境更适宜外周Treg的发育, 在肠道中天然T细胞受到抗原激活后诱发表达Foxp3. 在此过程中需要CD103＋树突状细胞和TGF-β的共同参与, 近年来维生素A的代谢产物维甲酸在提高Treg转化中的作用备受重视, 一方面他能上调T细胞上α4β7、CCR9等移居肠道的受体, 另一方面他能通过减少孤儿受体(RORγt)从而提高Treg的转化. 本文将对维甲酸和肠道免疫稳态作一综述.
具有调节功能的T细胞有很多亚群, 目前了解最多的是Foxp3+CD4+CD25+ Treg, 不同于传统意义上的Th1和Th2, 此类细胞同时具有免疫灭能和免疫抑制两大特征. 在人类和小鼠中, 表达Foxp3的Treg在维持免疫耐受的作用已被证实[1-6], 但是这种细胞的来源依然没有完全弄清. 以前大多数研究集中在从胸腺中发育而来的CD4+CD25+Foxp3+的Treg, 然而具有调节功能的T细胞也可来自于外周天然T细胞, 这些细胞的表型和从胸腺发育而来的Treg相似, 但是他们的形成方式不同[7-8]. 外周淋巴组织中Treg的产生需要抗原和TGF-β参与, 经TCR刺激后, CD4+CD25+T细胞表达Foxp3并获得了抑制活性[9-10]; 给予口服半抗原, 也能诱导外周Foxp3+的Treg的发育[7-11]. 肠道就是诱导外周Treg的主要器官之一, 肠道微环境有利于诱发Treg生成.
天然T细胞被抗原激活后, 变成效应、记忆T细胞, 并获得了移居到结外组织的能力. 在肠道抗原刺激下发育来的效应T细胞, 表达识别回归肠道的受体, 特别是α4β7、CCR9和TECK/CCL25受体, 导致这些细胞优先移居到小肠[12-16]. 同样被皮肤抗原刺激并诱导出效应T细胞, 表达能识别回归皮肤的受体, 如: 细胞因子受体CCR4和CCR10. Marjan在体内试验中已经证实, T细胞遇到抗原时的微环境, 决定了他优先移居的场所[17].
肠道相关淋巴组织(gut-associated lymphoid tissue, GALT)包括集合淋巴结、肠系膜淋巴结、肠黏膜固有层和肠上皮细胞, 其中的DCs被认为对外周Treg的发育和移居肠道起重要的作用[18]. 小肠黏膜固有层DCs含量丰富[19-20], MHCⅡ+CD11c+DCs占细胞总数的10%-15%, 而脾脏DCs只有不到细胞总数的3%. 80%以上黏膜固有层中DCs表达CD11b+[21], 不表达CD4和CD8α+[22]. 脾脏CD11b+DCs不表达CD103, CD11b-DCs弱表达CD103, 相反25%以上的黏膜固有层CD11b+DCs高表达CD103[22]. 集合淋巴结和肠系膜淋巴结中的DCs, 特异性的表达CD103+、CD8-、CD11b+. 正常小鼠肠系膜淋巴结(MLN)中CD103+的DCs, 能够提高天然T细胞转化成为Foxp3+ Treg的能力. 在CD4+CD25+ Treg调控的结肠炎试验中, 需要表达CD103 DCs的参与[23], 这一点提示CD103+的DCs在诱导Treg的反应中起到特定的作用. Janine et al[24]比较了从正常BALB/C小鼠分离来的CD103+和CD103- DCs, 诱导来源于DO11.10 SCID小鼠脾脏的CD4+ T细胞Foxp3+的表达, 发现其对T细胞的增殖和聚集的作用是相当的, 然而在培养的d 3和d 7, 利用流式细胞仪探测到了只有CD103+的DCs能够诱导Foxp3+的表达. 在培养中Foxp3+的诱导依赖于DCs的数量, CD103+ DCs的减少导致Foxp3+ Treg比例的减少. 除了诱导Foxp3的表达外, CD103+的DCs还能维持原有Foxp3+CD4+CD25+ T细胞的数量[24]. 从DO11.10BALB/C小鼠脾脏获得的CD4+CD25+T细胞, Foxp3+表达在TCR转基因(KJ-1.26+)部分, 在开始培养时, 75%的KJ-1.26+的T细胞表达Foxp3+, 随着培养时间的延长, 这个比例随之下降, 一个可能的原因是Foxp3-T细胞衍生物的污染, 并不是Foxp3基因的下调, 然而在培养中加入CD103+的DCs, 在培养的d 7 Foxp3表达的比例较开始时更高, 这点说明了除诱导Foxp3的表达外, CD103+DCs还能保持已有Foxp3的数量[24].
Jason et al为了进一步检测是否黏膜固有层DCs能够诱导Treg的转化, 分离脾脏(SP)和黏膜固有层(Lp)的DCs, 分别和CD4+eGFP-(强化绿色荧光蛋白)T细胞共培养, 培养基中分别加入抗CD3抗体、抗CD3抗体和TGF-β, 抗CD3抗体单独存在时不能诱导Foxp3的表达, 加入TGF-β后在两个培养基中均能诱导Foxp3的表达. 同时检测到LpDCs培养中诱导出Foxp3的表达显著的高于SpDCs[22]. 这点说明了在DCs诱导Treg发生过程中需要TGF-β的参与[7,25].
TGF-β除了维持外周Foxp3+CD4+CD25+ Treg的功能外[26], 还能诱导天然T细胞Foxp3的表达[24,27-29]. Janine et al在CD103+的DCs诱导Foxp3的试验中进一步研究了TGF-β的作用. 天然T细胞分别和CD103+、CD103-的DCs培养, 加入TGF-β抗体后, 完全阻断了Foxp3的表达, 揭示了TGF-β在表达CD103的DCs诱导转化Foxp3+Treg的过程中起到了调节功能. 他们还证实CD103+和CD103-DCs亚群功能是不同的, CD103+的DCs较CD103-的DCs, 能够产生更高水平的有活性的TGF-β[24]. 在CD103+的DCs培养中, 有足够的内源性TGF-β, 约10%天然T细胞转化为Foxp3+的T细胞. Janine et al进一步研究了加入不同浓度的外源性TGF-β对FOXP3转化的影响, 结果外源性的TGF-β的加入能够提高这种转化. 1 μg/L的TGF-β可使约50%的T细胞表达Foxp3, 然而在CD103-的DCs培养体系中加入TGF-β, 只有数量很少的Foxp3+T细胞产生, 这个比例显著低于CD103+的培养[24]. 尽管在试验中加入外源性的TGF-β已经是他的活化形式, 跳过了TGF-β的活化过程, 但是即使加入高浓度的活性TGF-β, 也不能使CD103-DCs诱导出与CD103+DCs相近水平的Foxp3, 提示了不是CD103-的DCs产生一种抑制因子, 就是缺乏一种重要的共因子.
维生素A参加了机体多种生物学过程, 包括视力、生殖、上皮细胞的分化、骨骼发育和免疫[30-31]. 维生素A对视力的作用依靠他的代谢产物, 11-顺-维A醛, 而对于其他系统的作用依靠他的代谢产物维甲酸, 主要是全反式维甲酸(all-trans-RA)和9-顺-维甲酸(9-cis-RA)[30]. 肝脏的伊藤细胞(Ito cells)是维生素A主要的储存库, 然而我们不知道, 是否这些细胞能够将维生素A转化成维甲酸, 如果可以那他们也参与了天然T细胞转化为Treg, 最近的研究揭示了他们有产生免疫的作用[32], 维生素A在肝脏中以视黄基酯的形式存在, 在进入血循环之前先被水解. 血浆中的视黄醇水平能保持在一定的范围内归功于肝脏的储存[33]. 然而肝脏细胞, 是否能够代谢维生素A成维甲酸, 并不清楚. 小鼠血浆中视黄醇的正常值是0.8-1.2 μmol[34], 约95%的血浆视黄醇和细胞连接蛋白相连, 进而进入细胞内氧化代谢产生维A醛[35], 随后转变成维甲酸并连接于细胞核的受体上, 一种是维甲酸受体(RAR), 包括α、β和γ3种表型, 另一种为类维生素A X受体(RXR), 包括α、β和γ3种表型[30-36]. 9-cis-RA能和RAR和RXR相连, all-trans-RA连接于RAR, 在高浓度时可以和RXR连接.
由视黄醇到维A醛的过程是可逆的, 这个过程被酒精脱氢酶(ADH)的亚家族催化[37]. ADH5整合素的mRNA表达在所有次级淋巴组织来源的树突状细胞上, 除此之外集合淋巴结的树突状细胞表达ADH1和ADH2整合素的mRNA. 由维A醛到维甲酸这个不可逆的反应过程被维A醛脱氢酶(RALDH)催化[35], 到目前为止可以肯定至少有4种该整合素表型, 其中有三种整合素表型能在次级淋巴组织中检测到, 集合淋巴结的树突状细胞表达RALDH1 mRNA, 肠系膜淋巴结的树突状细胞表达RALDH2 mRNA, RALDH3 mRNA在以上两个场所中都是弱表达[24,37]. 在外周淋巴结中以上各种RALDH mRNA的表达是相对低的, 仅仅弱表达RALDH2 mRNA. 这点说明肠系膜淋巴结和集合淋巴结的树突状细胞较外周淋巴结的树突状细胞, 有更强的催化产生维甲酸的能力.
维生素A缺乏的动物, 其胸腺和脾脏出现萎缩, 人体内维生素A缺乏会导致对多种微生物易感性的升高, 补充维生素A能够减少严重疾病的死亡率[38-40]. 以上作用主要依赖于维生素A的代谢产物-维甲酸及其衍生物, 他们参与了体内的免疫过程, 维甲酸除了能抑制B细胞和T细胞的增殖外[41-43], 还能减轻炎症反应, 临床上用维甲酸治疗套细胞淋巴瘤和痤疮分别依赖两者的作用机制[44]. 维甲酸及其衍生物的这种功能上的多效性, 主要是通过细胞核内维甲酸受体(RAR)和视黄醇X受体(RXR)介导的[45-46], 然而每种受体的作用还不是很清楚. Chen et al[47]用全反式维甲酸(ATRT)治疗C57BL6小鼠, 其脾脏和骨髓中CD19+细胞系显著的升高, 然而淋巴前体细胞总数是减少的, 从而提出ATRT在抑制祖细胞扩增的同时, 加速了他们进一步分化为B系淋巴细胞[47], 这也正是维生素A能增强抗感染免疫功能的作用机制[48], 同时在这个实验中, 利用PCR的方法证实了RAR-α介导了这一过程[47-49]. Dzhagalov et al[50]在RAR-γ缺陷小鼠体内实验中, 得出了RAR-γ对于T细胞和B细胞的发育不是必要的, 但是对于CD8+效应T细胞的分化和IFN-γ的产生是必要的. 除此之外Chen et al提出, 维甲酸通过提高细胞表面sIgG1和CD138的表达加速B细胞的成熟, 从而提高机体的体液免疫功能[51].
感染性疾病与婴幼儿持续性腹泻有密切关系, 已经证实维生素A在肠道免疫中发挥重要作用, 能够显著地减少该病的致死率. 肠系膜淋巴结和集合淋巴结的DCs分泌维生素A的代谢产物维甲酸, 经抗原刺激后能上调天然CD4+T细胞上α4β7整合素和CCR9的表达[17], 相反维生素A的缺乏, 则导致了淋巴组织中活性T细胞和记忆T细胞上α4β7和CCR9的减少, 同时还导致小肠黏膜固有层T细胞缺乏[37]. Makoto et al对比观察视黄醇缺乏的小鼠和对照小鼠体内维生素A的浓度分别为0.13±0.04 μmol和1.08±0.05 μmol[37], 维生素A缺乏的小鼠, 脾脏、肠系膜淋巴结、集合淋巴结中α4β7+CD4+记忆、活化T细胞显著减少, 而次级淋巴组织中α4β7-CD4+ T细胞并没有减少[17]. 在体外试验中all-trans-RA在0.1 nmol时能显著的提高T细胞上α4β7的表达, 9-cis-RA在1 nmol或更高浓度时能起到相似的作用, 视黄醇和维A醛, 在100 nmol或是更高浓度时才能起到相似的作用[37]. 另一方面维A醛脱氢酶抑制剂枸橼醛, 或者是维甲酸受体拮抗剂LE135/LE540(52), 能显著抑制DCs诱导T细胞上α4β7整合素和CCR9的表达, 而RXR拮抗剂PA452无相同的抑制作用[37-53], 由此说明了维甲酸和/或RAR参与了T细胞移居肠道的过程. 因为α4β7整合素能和肠道血管的黏膜固有层细胞黏附分子连接[54], CCR9能和小肠隐窝上皮的胸腺表达因子配体连接[55], 所以可以理解为经抗原刺激后的T淋巴细胞, 在肠道相关CD103+的DCs的作用下, 通过维甲酸上调了α4β7和CCR9的表达, 从而移居到GALT中.
Micah et al研究发现在天然T细胞转化为Foxp3+T细胞的过程中, 维生素A的参与是一个重要的因素[56]. 在CD4+ Foxp3-转化为CD4+ Foxp3+的体外试验中, 含有IL-2和TGF-β的培养体系中FOXP3的转化率为15%-50%, 加入维甲酸后转化率可>90%或更高, 另一方面维甲酸受体拮抗剂LE135/LE540能减少这种转化[37]. 在加入外源性TGF-β的CD103+ 和CD103-DCs的培养体系中, CD103+的培养体系中诱导Foxp3+T细胞的比例大于CD103-的培养基, 然而在外源性TGF-β和维甲酸都存在的情况下, 两种培养体系中Foxp3+T细胞的数量和比例相似[24]. 由此说明了在T细胞转化为Foxp3+T细胞的过程中维甲酸是共因子[2].
Micah et al进一步研究发现维甲酸单独并不能引发Foxp3的转化[22,24,56], 需要TGF-β和IL-2的参与[9-10,57], 在这个试验中, IL-2的浓度不变, 加入不同浓度条件下的TGF-β, 在相同的培养条件下维甲酸的加入显著提高了转化率. 同时发现维甲酸在小于1 nmol时作用显著, 在30-100 nmol时维甲酸能抑制T细胞的增殖[58].
孤儿受体(RORγt)参与了Th17的基因转录[59-60], 他和维甲酸诱导Treg的产生相关. Mucida et al的体外研究证实, TGF-β和IL-6共同存在的情况下[61], T细胞转化为辅助性Th17细胞[62-64], Th17和Treg作用相反, 能加强主动免疫和炎症反应, 同炎症性肠病、类风湿性关节炎、特异性的变态反应密切相关[65-66]. 然而如在培养初期加入维甲酸, T细胞则转化为Treg[67]. 为了验证维甲酸能调控RORγt, 在含有炎症刺激因子的培养基中, 加入TGF-β能诱导出高水平的RORγt, 然而加入维甲酸后这种表达明显的减少. 在体内试验中进一步验证维甲酸对Th17增殖的抑制作用, 给受试小鼠口服致病源, 并分别经RA和RAR抑制剂LE540处理[68], 在接受RA治疗的小鼠能检测到T17细胞减少, 而接受LE540治疗的小鼠和对照组比较没有明显的不同. 综合以上的试验结果, 维甲酸在体内和体外均可抑制Th17细胞的增殖, 从而使T细胞转化为Treg, 其作用机制是通过直接减少RORγt[67].
体外产生的Foxp3+CD4 T细胞是否能在体内抑制效应T细胞, Mucida et al[67]做了共转移试验, 用CD45RBHICD4 T细胞在免疫缺陷的小鼠体内诱导出结肠炎, 同时将在不同环境下诱导出的CD4 T细胞转移进小鼠体内. 结果在没有细胞因子的环境下激活CD4 T细胞和CD45RBHICD4细胞能导致结肠炎, 相反如果共转移的是在TGF-β参与下激活的CD4 T细胞, 能部分的阻止本病的发生, 如果共转移的是在TGF-β和维甲酸都存在的环境下激活的CD4 T细胞, 则不发生该病[67], 这说明了在体外TGF-β和维甲酸都存在的情况下诱导产生的Foxp3+的T细胞在体内也能发挥抑制效应细胞的功能[56,67].
Treg在免疫耐受中的作用是肯定的, 在体外培养中DCs能诱导并扩增调节性T细胞, 且这一过程依靠TGF-β的参与, 维甲酸的加入可加强这种转化率, 在体外扩增的Treg在体内仍可抑制效应T细胞的功能, 从而达到抑制自身免疫损伤的作用. 目前除了维甲酸在体内外的研究取得一定的成果外, 近期有证据表明了低于生理水平的维甲酸可能导致了TGF-β功能的失调, 提高RORγt的表达, 使得Th17细胞的增殖多于调节性T细胞, 引发了免疫功能的失衡. 这些结果为我们治疗免疫性疾病提供了新的思路, 由于维甲酸的副作用, 维甲酸受体激活剂可能更适用于体内试验. 此外是否维甲酸只能作用于天然T细胞转化为Treg, 能否用于转化已经激活的或是分化的T细胞, 从而阻断已经发生不必要的免疫反应. 因为部分免疫缺陷的患者体内Treg的数量是正常的, RORγt的提出使我们有了治疗的新视角, 那就是能否通过减少RORγt抑制Th17细胞的增殖, 从而达到治疗免疫性疾病.
为了维持体内的免疫稳态, 小肠的免疫系统具备了抗炎免疫调节机能, 从而避免机体受损. 肠道是大量Foxp3+的Treg的定居场所, 它在肠道免疫的建立和维护中发挥着不可或缺的作用.
白爱平, 副教授, 南昌大学第一附属医院消化内科
近年来维甲酸在提高Treg转化中的作用备受重视, 一方面他能上调T细胞上α4β7、CCR9等移居肠道的受体, 另一方面他能通过减少孤儿受体(RORγt)从而提高Treg的转化.
以前的研究多集中在胸腺来源的Treg, 现已证实可来自外周天然T细胞, 且肠道微环境更适宜他的发育, 在此过程中需要CD103+树突状细胞和TGF-β的共同参与.
本文有利于进一步了解肠道免疫的调节机制.
本文选题准确, 但文章仅对维甲酸在调节性T细胞产生过程中的作用进行了综述, 缺少对维甲酸在机体免疫反应中的作用部分.
编辑: 程剑侠 电编: 吴鹏朕
| 1. | Powrie F, Read S, Mottet C, Uhlig H, Maloy K. Control of immune pathology by regulatory T cells. Novartis Found Symp. 2003;252:92-8; discussion 98-105, 106-14. [PubMed] |
| 2. | Coombes JL, Robinson NJ, Maloy KJ, Uhlig HH, Powrie F. Regulatory T cells and intestinal homeostasis. Immunol Rev. 2005;204:184-194. [PubMed] [DOI] |
| 3. | Fantini MC, Becker C, Tubbe I, Nikolaev A, Lehr HA, Galle P, Neurath MF. Transforming growth factor beta induced FoxP3+ regulatory T cells suppress Th1 mediated experimental colitis. Gut. 2006;55:671-680. [PubMed] [DOI] |
| 4. | Ochando JC, Homma C, Yang Y, Hidalgo A, Garin A, Tacke F, Angeli V, Li Y, Boros P, Ding Y. Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts. Nat Immunol. 2006;7:652-662. [PubMed] [DOI] |
| 5. | Karim M, Kingsley CI, Bushell AR, Sawitzki BS, Wood KJ. Alloantigen-induced CD25+CD4+ regulatory T cells can develop in vivo from CD25-CD4+ precursors in a thymus-independent process. J Immunol. 2004;172:923-928. [PubMed] [DOI] |
| 6. | Khattri R, Cox T, Yasayko SA, Ramsdell F. An essential role for Scurfin in CD4+CD25+ T regulatory cells. Nat Immunol. 2003;4:337-342. [PubMed] [DOI] |
| 7. | Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig MC, von Boehmer H. Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol. 2005;6:1219-1227. [PubMed] [DOI] |
| 8. | Apostolou I, von Boehmer H. In vivo instruction of suppressor commitment in naive T cells. J Exp Med. 2004;199:1401-1408. [PubMed] [DOI] |
| 9. | Chen W, Jin W, Hardegen N, Lei KJ, Li L, Marinos N, McGrady G, Wahl SM. Conversion of peripheral CD4+CD25- naive T cells to CD4+CD25+ regulatory T cells by TGF-beta induction of transcription factor Foxp3. J Exp Med. 2003;198:1875-1886. [PubMed] [DOI] |
| 10. | Fantini MC, Becker C, Monteleone G, Pallone F, Galle PR, Neurath MF. Cutting edge: TGF-beta induces a regulatory phenotype in CD4+CD25- T cells through Foxp3 induction and down-regulation of Smad7. J Immunol. 2004;172:5149-5153. [PubMed] [DOI] |
| 11. | Sun JB, Raghavan S, Sjöling A, Lundin S, Holmgren J. Oral tolerance induction with antigen conjugated to cholera toxin B subunit generates both Foxp3+CD25+ and Foxp3-CD25- CD4+ regulatory T cells. J Immunol. 2006;177:7634-7644. [PubMed] [DOI] |
| 12. | Johansson-Lindbom B, Svensson M, Wurbel MA, Malissen B, Márquez G, Agace W. Selective generation of gut tropic T cells in gut-associated lymphoid tissue (GALT): requirement for GALT dendritic cells and adjuvant. J Exp Med. 2003;198:963-969. [PubMed] [DOI] |
| 13. | Johansson-Lindbom B, Svensson M, Pabst O, Palmqvist C, Marquez G, Förster R, Agace WW. Functional specialization of gut CD103+ dendritic cells in the regulation of tissue-selective T cell homing. J Exp Med. 2005;202:1063-1073. [PubMed] [DOI] |
| 14. | Siewert C, Menning A, Dudda J, Siegmund K, Lauer U, Floess S, Campbell DJ, Hamann A, Huehn J. Induction of organ-selective CD4+ regulatory T cell homing. Eur J Immunol. 2007;37:978-989. [PubMed] [DOI] |
| 15. | Mora JR, Bono MR, Manjunath N, Weninger W, Cavanagh LL, Rosemblatt M, Von Andrian UH. Selective imprinting of gut-homing T cells by Peyer's patch dendritic cells. Nature. 2003;424:88-93. [PubMed] [DOI] |
| 16. | Svensson M, Marsal J, Ericsson A, Carramolino L, Brodén T, Márquez G, Agace WW. CCL25 mediates the localization of recently activated CD8alphabeta(+) lymphocytes to the small-intestinal mucosa. J Clin Invest. 2002;110:1113-1121. [PubMed] [DOI] |
| 17. | Mora JR, von Andrian UH. Retinoic acid: an educational "vitamin elixir" for gut-seeking T cells. Immunity. 2004;21:458-460. [PubMed] [DOI] |
| 18. | Stagg AJ, Kamm MA, Knight SC. Intestinal dendritic cells increase T cell expression of alpha4beta7 integrin. Eur J Immunol. 2002;32:1445-1454. [PubMed] [DOI] |
| 19. | Chirdo FG, Millington OR, Beacock-Sharp H, Mowat AM. Immunomodulatory dendritic cells in intestinal lamina propria. Eur J Immunol. 2005;35:1831-1840. [PubMed] [DOI] |
| 20. | Pavli P, Woodhams CE, Doe WF, Hume DA. Isolation and characterization of antigen-presenting dendritic cells from the mouse intestinal lamina propria. Immunology. 1990;70:40-47. [PubMed] |
| 21. | Niess JH, Reinecker HC. Lamina propria dendritic cells in the physiology and pathology of the gastrointestinal tract. Curr Opin Gastroenterol. 2005;21:687-691. [PubMed] [DOI] |
| 22. | Sun CM, Hall JA, Blank RB, Bouladoux N, Oukka M, Mora JR, Belkaid Y. Small intestine lamina propria dendritic cells promote de novo generation of Foxp3 T reg cells via retinoic acid. J Exp Med. 2007;204:1775-1785. [PubMed] [DOI] |
| 23. | Annacker O, Coombes JL, Malmstrom V, Uhlig HH, Bourne T, Johansson-Lindbom B, Agace WW, Parker CM, Powrie F. Essential role for CD103 in the T cell-mediated regulation of experimental colitis. J Exp Med. 2005;202:1051-1061. [PubMed] [DOI] |
| 24. | Coombes JL, Siddiqui KR, Arancibia-Cárcamo CV, Hall J, Sun CM, Belkaid Y, Powrie F. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-beta and retinoic acid-dependent mechanism. J Exp Med. 2007;204:1757-1764. [PubMed] [DOI] |
| 25. | Wan YY, Flavell RA. Identifying Foxp3-expressing suppressor T cells with a bicistronic reporter. Proc Natl Acad Sci USA. 2005;102:5126-5131. [PubMed] [DOI] |
| 26. | Marie JC, Letterio JJ, Gavin M, Rudensky AY. TGF-beta1 maintains suppressor function and Foxp3 expression in CD4+CD25+ regulatory T cells. J Exp Med. 2005;201:1061-1067. [PubMed] [DOI] |
| 27. | Cobbold SP, Castejon R, Adams E, Zelenika D, Graca L, Humm S, Waldmann H. Induction of foxP3+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants. J Immunol. 2004;172:6003-6010. [PubMed] [DOI] |
| 28. | Fu S, Zhang N, Yopp AC, Chen D, Mao M, Chen D, Zhang H, Ding Y, Bromberg JS. TGF-beta induces Foxp3 + T-regulatory cells from CD4 + CD25 - precursors. Am J Transplant. 2004;4:1614-1627. [PubMed] [DOI] |
| 29. | Rao PE, Petrone AL, Ponath PD. Differentiation and expansion of T cells with regulatory function from human peripheral lymphocytes by stimulation in the presence of TGF-{beta}. J Immunol. 2005;174:1446-1455. [PubMed] [DOI] |
| 30. | Kastner P, Mark M, Chambon P. Nonsteroid nuclear receptors: what are genetic studies telling us about their role in real life? Cell. 1995;83:859-869. [PubMed] [DOI] |
| 31. | Napoli JL. Interactions of retinoid binding proteins and enzymes in retinoid metabolism. Biochim Biophys Acta. 1999;1440:139-162. [PubMed] [DOI] |
| 32. | Winau F, Hegasy G, Weiskirchen R, Weber S, Cassan C, Sieling PA, Modlin RL, Liblau RS, Gressner AM, Kaufmann SH. Ito cells are liver-resident antigen-presenting cells for activating T cell responses. Immunity. 2007;26:117-129. [PubMed] [DOI] |
| 33. | von Boehmer H. Oral tolerance: is it all retinoic acid? J Exp Med. 2007;204:1737-1739. [PubMed] [DOI] |
| 34. | Molrine DC, Polk DB, Ciamarra A, Phillips N, Ambrosino DM. Impaired human responses to tetanus toxoid in vitamin A-deficient SCID mice reconstituted with human peripheral blood lymphocytes. Infect Immun. 1995;63:2867-2872. [PubMed] |
| 35. | Duester G. Families of retinoid dehydrogenases regulating vitamin A function: production of visual pigment and retinoic acid. Eur J Biochem. 2000;267:4315-4324. [PubMed] [DOI] |
| 36. | Mangelsdorf DJ, Evans RM. The RXR heterodimers and orphan receptors. Cell. 1995;83:841-850. [PubMed] [DOI] |
| 37. | Iwata M, Hirakiyama A, Eshima Y, Kagechika H, Kato C, Song SY. Retinoic acid imprints gut-homing specificity on T cells. Immunity. 2004;21:527-538. [PubMed] [DOI] |
| 38. | Semba RD, Ndugwa C, Perry RT, Clark TD, Jackson JB, Melikian G, Tielsch J, Mmiro F. Effect of periodic vitamin A supplementation on mortality and morbidity of human immunodeficiency virus-infected children in Uganda: A controlled clinical trial. Nutrition. 2005;21:25-31. [PubMed] [DOI] |
| 39. | Villamor E, Fawzi WW. Effects of vitamin a supplementation on immune responses and correlation with clinical outcomes. Clin Microbiol Rev. 2005;18:446-464. [PubMed] [DOI] |
| 40. | Grubesic RB, Selwyn BJ. Vitamin A supplementation and health outcomes for children in Nepal. J Nurs Scholarsh. 2003;35:15-20. [PubMed] [DOI] |
| 41. | Ludányi K, Nagy ZS, Alexa M, Reichert U, Michel S, Fésüs L, Szondy Z. Ligation of RARgamma inhibits proliferation of phytohaemagglutinin-stimulated T-cells via down-regulating JAK3 protein levels. Immunol Lett. 2005;98:103-113. [PubMed] [DOI] |
| 42. | Kupumbati TS, Cattoretti G, Marzan C, Farias EF, Taneja R, Mira-y-Lopez R. Dominant negative retinoic acid receptor initiates tumor formation in mice. Mol Cancer. 2006;5:12. [PubMed] [DOI] |
| 43. | Chen Q, Ross AC. Vitamin A and immune function: retinoic acid modulates population dynamics in antigen receptor and CD38-stimulated splenic B cells. Proc Natl Acad Sci USA. 2005;102:14142-14149. [PubMed] [DOI] |
| 44. | Guidoboni M, Zancai P, Cariati R, Rizzo S, Dal Col J, Pavan A, Gloghini A, Spina M, Cuneo A, Pomponi F. Retinoic acid inhibits the proliferative response induced by CD40 activation and interleukin-4 in mantle cell lymphoma. Cancer Res. 2005;65:587-595. [PubMed] |
| 45. | Maret M, Ruffie C, Periquet B, Campo AM, Menevret M, Phelep A, Dziewiszek K, Druilhe A, Pretolani M. Liposomal retinoic acids modulate asthma manifestations in mice. J Nutr. 2007;137:2730-2736. [PubMed] |
| 46. | Morikawa K, Nonaka M. All-trans-retinoic acid accelerates the differentiation of human B lymphocytes maturing into plasma cells. Int Immunopharmacol. 2005;5:1830-1838. [PubMed] [DOI] |
| 47. | Chen X, Esplin BL, Garrett KP, Welner RS, Webb CF, Kincade PW. Retinoids accelerate B lineage lymphoid differentiation. J Immunol. 2008;180:138-145. [PubMed] [DOI] |
| 48. | Wei D, Yang Y, Wang WP. [Effect of retinoic acid on the development of B cells from lymph nodes of young children and the pathway of the effect]. Zhonghua Erke Zazhi. 2005;43:360-363. [PubMed] |
| 49. | Blomhoff HK. Vitamin A regulates proliferation and apoptosis of human T- and B-cells. Biochem Soc Trans. 2004;32:982-984. [PubMed] [DOI] |
| 50. | Dzhagalov I, Chambon P, He YW. Regulation of CD8+ T lymphocyte effector function and macrophage inflammatory cytokine production by retinoic acid receptor gamma. J Immunol. 2007;178:2113-2121. [PubMed] [DOI] |
| 51. | Chen Q, Ross AC. Retinoic acid promotes mouse splenic B cell surface IgG expression and maturation stimulated by CD40 and IL-4. Cell Immunol. 2007;249:37-45. [PubMed] [DOI] |
| 52. | Umemiya H, Fukasawa H, Ebisawa M, Eyrolles L, Kawachi E, Eisenmann G, Gronemeyer H, Hashimoto Y, Shudo K, Kagechika H. Regulation of retinoidal actions by diazepinylbenzoic acids. Retinoid synergists which activate the RXR-RAR heterodimers. J Med Chem. 1997;40:4222-4234. [PubMed] [DOI] |
| 53. | Takahashi B, Ohta K, Kawachi E, Fukasawa H, Hashimoto Y, Kagechika H. Novel retinoid X receptor antagonists: specific inhibition of retinoid synergism in RXR-RAR heterodimer actions. J Med Chem. 2002;45:3327-3330. [PubMed] [DOI] |
| 54. | Miyasaka M, Tanaka T. Lymphocyte trafficking across high endothelial venules: dogmas and enigmas. Nat Rev Immunol. 2004;4:360-370. [PubMed] [DOI] |
| 55. | Wurbel MA, Philippe JM, Nguyen C, Victorero G, Freeman T, Wooding P, Miazek A, Mattei MG, Malissen M, Jordan BR. The chemokine TECK is expressed by thymic and intestinal epithelial cells and attracts double- and single-positive thymocytes expressing the TECK receptor CCR9. Eur J Immunol. 2000;30:262-271. [PubMed] [DOI] |
| 56. | Benson MJ, Pino-Lagos K, Rosemblatt M, Noelle RJ. All-trans retinoic acid mediates enhanced T reg cell growth, differentiation, and gut homing in the face of high levels of co-stimulation. J Exp Med. 2007;204:1765-1774. [PubMed] [DOI] |
| 57. | Zheng SG, Wang JH, Gray JD, Soucier H, Horwitz DA. Natural and induced CD4+CD25+ cells educate CD4+CD25- cells to develop suppressive activity: the role of IL-2, TGF-beta, and IL-10. J Immunol. 2004;172:5213-5221. [PubMed] [DOI] |
| 58. | Racke MK, Burnett D, Pak SH, Albert PS, Cannella B, Raine CS, McFarlin DE, Scott DE. Retinoid treatment of experimental allergic encephalomyelitis. IL-4 production correlates with improved disease course. J Immunol. 1995;154:450-458. [PubMed] |
| 59. | Ivanov II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR. The orphan nuclear receptor RORgammat directs the differentiation program of proinflammatory IL-17+ T helper cells. Cell. 2006;126:1121-1133. [PubMed] [DOI] |
| 60. | Elson CO, Cong Y, Weaver CT, Schoeb TR, McClanahan TK, Fick RB, Kastelein RA. Monoclonal anti-interleukin 23 reverses active colitis in a T cell-mediated model in mice. Gastroenterology. 2007;132:2359-2370. [PubMed] [DOI] |
| 61. | Kimura A, Naka T, Kishimoto T. IL-6-dependent and -independent pathways in the development of interleukin 17-producing T helper cells. Proc Natl Acad Sci USA. 2007;104:12099-12104. [PubMed] [DOI] |
| 62. | Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stockinger B. TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL-17-producing T cells. Immunity. 2006;24:179-189. [PubMed] [DOI] |
| 63. | Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441:235-238. [PubMed] [DOI] |
| 64. | Mangan PR, Harrington LE, O'Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT. Transforming growth factor-beta induces development of the T(H)17 lineage. Nature. 2006;441:231-234. [PubMed] [DOI] |
| 65. | Kolls JK, Lindén A. Interleukin-17 family members and inflammation. Immunity. 2004;21:467-476. [PubMed] [DOI] |
| 66. | Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, McClanahan T, Kastelein RA, Cua DJ. IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med. 2005;201:233-240. [PubMed] [DOI] |
| 67. | Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H. Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid. Science. 2007;317:256-260. [PubMed] [DOI] |
| 68. | Li Y, Hashimoto Y, Agadir A, Kagechika H, Zhang Xk. Identification of a novel class of retinoic acid receptor beta-selective retinoid antagonists and their inhibitory effects on AP-1 activity and retinoic acid-induced apoptosis in human breast cancer cells. J Biol Chem. 1999;274:15360-15366. [PubMed] [DOI] |