Interruption of dendritic cell-mediated TIM-4 signaling induces regulatory T cells and promotes skin allograft survival.
Interruption of dendritic cell-mediated TIM-4 signaling induces regulatory T cells and promotes skin allograft survival.
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DOI：
10.4049/jimmunol.1300992
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发表时间：
2013-10-15
期刊：
影响因子：
--
通讯作者：
Najafian N
中科院分区：
文献类型：
--
作者：
Yeung MY;McGrath MM;Nakayama M;Shimizu T;Boenisch O;Magee CN;Abdoli R;Akiba H;Ueno T;Turka LA;Najafian N
树突状细胞（DC）是免疫反应的主要架构师，诱导炎症或耐受性免疫，这取决于它们的活化状态。因此，DC是非常有吸引力的治疗靶点，并且可能具有控制有害免疫应答的潜力。TIM-4在抗原呈递细胞上表达，在体内具有复杂的功能，既作为共刺激分子又作为磷脂酰丝氨酸（PS）受体。TIM-4共刺激对T细胞活化的影响尚不清楚。在这里，我们证明了抗体阻断DC表达的TIM-4导致体外和体内从幼稚CD 4 + T细胞诱导的iT细胞增加。iTreg诱导通过抑制IL-4/STAT 6/Gata 3诱导的Th 2分化而发生。此外，在先前活化的DC上阻断TIM-4仍然导致iTreg诱导增加。在TIM-4阻断下诱导的iT细胞具有与对照相当的效力，并且在过继转移后，显著延长了体内皮肤同种异体移植物存活。在RAG−/−受体的皮肤同种异体移植物过继转移CD 4 + T细胞，我们表明，体内TIM-4阻断与移植物存活延长三倍相关。此外，在该皮肤移植小鼠模型中，观察到同种异体特异性iT细胞的诱导增加和T效应子应答减少，Th 1和Th 2应答减少。这种增强的同种异体移植物存活率和同种异体反应的促耐受性偏斜严重依赖于体内幼稚CD 4+转化为T细胞。总的来说，这些研究确定阻断DC表达的TIM-4作为一种新的策略，其具有在体内诱导调节性免疫的能力。
Dendritic cells (DCs) are the central architects of the immune response, inducing inflammatory or tolerogenic immunity, dependent upon their activation status. As such, DCs are highly attractive therapeutic targets and may hold the potential to control detrimental immune responses. TIM-4, expressed on antigen presenting cells, has complex functions in vivo, acting both as a costimulatory molecule and a phosphatidylserine (PS) receptor. The effect of TIM-4 costimulation on T cell activation remains unclear. Here, we demonstrate that antibody blockade of DC-expressed TIM-4 leads to increased induction of iTregs from naïve CD4+ T cells, both in vitro and in vivo. iTreg induction occurs through suppression of IL-4/STAT6/Gata3 induced Th2 differentiation. In addition, blockade of TIM-4 on previously activated DCs still leads to increased iTreg induction. iTregs induced under TIM-4 blockade have equivalent potency to control and upon adoptive transfer, significantly prolong skin allograft survival in vivo. In RAG−/− recipients of skin allografts adoptively transferred with CD4+ T cells, we show that TIM-4 blockade in vivo is associated with a three-fold prolongation in allograft survival. Furthermore, in this mouse model of skin transplantation, increased induction of allospecific iTregs and a reduction in T effector responses were observed, with decreased Th1 and Th2 responses. This enhanced allograft survival and pro-tolerogenic skewing of the alloresponse is critically dependent upon conversion of naïve CD4+ to Tregs in vivo. Collectively, these studies identify blockade of DC-expressed TIM-4 as a novel strategy which holds the capacity to induce regulatory immunity in vivo.
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DOI：
10.1084/jem.20082394
发表时间：
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期刊：
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影响因子：
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