TIM-3: a novel regulatory molecule of alloimmune activation.
TIM-3: a novel regulatory molecule of alloimmune activation.
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DOI：
10.4049/jimmunol.0903435
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发表时间：
2010-11-15
期刊：
影响因子：
--
通讯作者：
Najafian N
中科院分区：
文献类型：
--
作者：
Boenisch O;D'Addio F;Watanabe T;Elyaman W;Magee CN;Yeung MY;Padera RF;Rodig SJ;Murayama T;Tanaka K;Yuan X;Ueno T;Jurisch A;Mfarrej B;Akiba H;Yagita H;Najafian N
T细胞IG结构域和粘蛋白结构域（TIM）-3先前已被确定为Th 1应答和免疫耐受的中心调节因子。在这项研究中，我们研究了在同种异体排斥反应中的功能，在小鼠模型的血管化心脏移植。TIM-3在树突状细胞和天然调节性T细胞（TCFs）上组成型表达，但仅在急性排斥移植物受体的CD 4 + FoxP 3 −和CD 8 + T细胞上检测到。阻断性抗TIM-3 mAb仅在存在宿主CD 4 + T细胞的情况下加速同种异体移植物排斥反应。加速排斥反应伴随着同种异体反应性IFN-γ-、IL-6-和IL-17产生脾细胞的频率增加，针对同种异体抗原的CD 8+细胞毒性增强，同种异体抗体产生增加，以及外周和移植物内Treg/效应T细胞比率下降。TIM-3阻断后，CD 4 + T细胞产生的IL-6增加在加速排斥反应中起着重要作用。使用已建立的同种异体反应性TCR转基因模型，阻断TIM-3增加同种异体特异性效应T细胞，增强Th 1和Th 17极化，并导致同种异体特异性TCR总数的频率降低。后者是由于抑制诱导适应性T细胞，而不是阻止异源性天然T细胞的扩增。在体外，靶向TIM-3没有抑制nTreg介导的Th 1同种异体反应性细胞的抑制，但增加了效应T细胞产生IL-17。总之，TIM-3通过其广泛调节CD 4 + T细胞分化的能力是同种免疫的关键调节分子，从而重新校准同种免疫应答的效应器和调节臂。
T cell Ig domain and mucin domain (TIM)-3 has previously been established as a central regulator of Th1 responses and immune tolerance. In this study, we examined its functions in allograft rejection in a murine model of vascularized cardiac transplantation. TIM-3 was constitutively expressed on dendritic cells and natural regulatory T cells (Tregs) but only detected on CD4+FoxP3− and CD8+ T cells in acutely rejecting graft recipients. A blocking anti–TIM-3 mAb accelerated allograft rejection only in the presence of host CD4+ T cells. Accelerated rejection was accompanied by increased frequencies of alloreactive IFN-γ–, IL-6–, and IL-17–producing splenocytes, enhanced CD8+ cytotoxicity against alloantigen, increased alloantibody production, and a decline in peripheral and intragraft Treg/effector T cell ratio. Enhanced IL-6 production by CD4+ T cells after TIM-3 blockade plays a central role in acceleration of rejection. Using an established alloreactivity TCR transgenic model, blockade of TIM-3 increased allospecific effector T cells, enhanced Th1 and Th17 polarization, and resulted in a decreased frequency of overall number of allospecific Tregs. The latter is due to inhibition in induction of adaptive Tregs rather than prevention of expansion of allospecific natural Tregs. In vitro, targeting TIM-3 did not inhibit nTreg-mediated suppression of Th1 alloreactive cells but increased IL-17 production by effector T cells. In summary, TIM-3 is a key regulatory molecule of alloimmunity through its ability to broadly modulate CD4+ T cell differentiation, thus recalibrating the effector and regulatory arms of the alloimmune response.
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影响因子：
64.8
作者：
Bettelli, E;Carrier, YJ;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
4.4
作者：
Oikawa, Tsunekazu;Kamimura, Yosuke;Azuma, Miyuki
通讯作者：
Azuma, Miyuki
影响因子：
30.5
作者：
Sabatos, CA;Chakravarti, S;Kuchroo, VK
通讯作者：
Kuchroo, VK
影响因子：
56.9
作者：
Pasare, C;Medzhitov, R
通讯作者：
Medzhitov, R
DOI：
10.4049/jimmunol.0803842
发表时间：
2009-05-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Chen L;Ahmed E;Wang T;Wang Y;Ochando J;Chong AS;Alegre ML
通讯作者：
Alegre ML