Fyn promotes Th17 differentiation by regulating the kinetics of RORγt and Foxp3 expression.
Fyn promotes Th17 differentiation by regulating the kinetics of RORγt and Foxp3 expression.
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DOI：
10.4049/jimmunol.1102241
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发表时间：
2012-06-01
期刊：
影响因子：
--
通讯作者：
Stein PL
中科院分区：
文献类型：
--
作者：
Ueda A;Zhou L;Stein PL
TH 17细胞构成促炎性CD 4 + T细胞亚群，其对于微生物清除是重要的，但也涉及作为各种自身免疫病理的传播者。有证据表明，TH 17细胞与免疫抑制性CD 4+诱导型调节性T细胞（iTREG）共有共同的祖细胞，并且这两个亚群的发育途径受到免疫调节。在这项研究中，我们证明Src家族酪氨酸激酶Fyn有助于调节TH 17/TREG平衡。当放置在TH 17偏置条件下时，来自fyn−/−小鼠的CD 4 + T细胞的IL 17水平降低，但TREG转录因子Foxp 3的表达增加。IL 17表达缺陷的发生与异位Foxp 3表达无关，并且与RORγt上调延迟和不能维持正常STAT 3激活相关。Fyn缺陷型TH 17细胞还表现出IL 23 r、IL 21、Rora和Irf 4的延迟上调，以及Socs 3的异常表达，这表明Fyn可能在有助于TH 17极化的多种分子途径的上游起作用。与同窝对照组相比，fyn−/−小鼠大肠固有层中的IL 17 + CD 4 + T细胞较少。此外，在将WT或fyn−/− naïve CD 4 + T细胞转移到Rag 1 −/−宿主中后，接受fyn−/−细胞的受体具有较少的IL 17产生T细胞，表明Fyn也可以调节体内TH 17分化。这些结果确定Fyn作为TH 17和Treg细胞亚群之间的发育平衡的可能的新调节剂。
TH17 cells constitute a pro-inflammatory CD4+ T-cell subset that is important for microbial clearance, but also are implicated as propagators of various autoimmune pathologies. Evidence suggests that TH17 cells share common progenitors with immunosuppressive CD4+ inducible regulatory T-cells (iTREG), and that the developmental pathways of these two subsets are reciprocally regulated. In this study, we show evidence that the Src-family tyrosine kinase Fyn helps regulate this TH17/TREG balance. When placed under TH17-skewing conditions, CD4+ T-cells from fyn−/− mice had decreased levels of IL17, but increased expression of the TREG transcription factor Foxp3. The defect in IL17 expression occurred independently of the ectopic Foxp3 expression, and correlated with a delay in RORγt upregulation and an inability to maintain normal STAT3 activation. Fyn-deficient TH17 cells also exhibited delayed upregulation of Il23r, Il21, Rora, and Irf4, as well as aberrant expression of Socs3, suggesting that Fyn may function upstream of a variety of molecular pathways that contribute to TH17 polarization. The fyn−/− mice had fewer IL17+CD4+ T-cells in the large intestinal lamina propria compared to littermate controls. Furthermore, after transfer of either WT or fyn−/− naïve CD4+ T-cells into Rag1−/− hosts, recipients receiving fyn−/− cells had fewer IL17-producing T-cells, indicating that Fyn may also regulate TH17 differentiation in vivo. These results identify Fyn as a possible novel regulator of the developmental balance between the TH17 and TREG cell subsets.
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影响因子：
64.5
作者：
Ivanov, Ivaylo I.;McKenzie, Brent S.;Littman, Dan R.
通讯作者：
Littman, Dan R.
影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
LCK通过对T-BET和GATA-3的影响介导Th2的分化。
DOI：
10.4049/jimmunol.0901282
发表时间：
2010-04-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Kemp KL;Levin SD;Bryce PJ;Stein PL
通讯作者：
Stein PL
影响因子：
32.4
作者：
Bird, JJ;Brown, DR;Reiner, SL
通讯作者：
Reiner, SL
影响因子：
4.8
作者：
Ichiyama, Kenji;Yoshida, Hideyuki;Kobayashi, Takashi
通讯作者：
Kobayashi, Takashi