T and B cell hyperactivity and autoimmunity associated with niche-specific defects in apoptotic body clearance in TIM-4-deficient mice
T and B cell hyperactivity and autoimmunity associated with niche-specific defects in apoptotic body clearance in TIM-4-deficient mice
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DOI：
10.1073/pnas.0910359107
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发表时间：
2010-05-11
影响因子：
11.1
通讯作者：
Kuchroo, Vijay K.
中科院分区：
文献类型：
--
作者：
Rodriguez-Manzanet, Roselynn;Sanjuan, Miguel A.;Kuchroo, Vijay K.
TIM-4是在抗原呈递细胞上表达的TIM家族的成员，与暴露在凋亡小体表面上的磷脂酰丝氨酸结合。然而，这种相互作用在体内的意义仍然是未知的，因为其他受体已被牵连在凋亡小体的清除，并可以补偿TIM-4的缺陷在体内。在这项研究中，我们描述了TIM-4缺陷小鼠的产生，并解决TIM-4是否在体内发挥独特的功能。我们发现，TIM-4（-/-）腹腔巨噬细胞和B-1细胞在体外不能有效地吞噬凋亡小体，在体内也不能清除凋亡小体。TIM-4缺陷型小鼠具有过度活跃的T和B细胞，血清IG水平升高，并产生针对双链DNA的抗体。两者合计，我们表明，TIM-4是至关重要的清除凋亡小体在体内，缺乏TIM-4的结果在异常的持久性凋亡小体，导致失调的淋巴细胞活化和全身性自身免疫的迹象。
TIM-4, a member of the TIM family expressed on antigen-presenting cells, binds to phosphatidylserine exposed on the surface of apoptotic bodies. However, the significance of this interaction in vivo remains unknown because other receptors have been implicated in the clearance of apoptotic bodies and could compensate for the TIM-4 deficiency in vivo. In this study, we describe the generation of TIM-4-deficient mice and address whether TIM-4 serves a unique function in vivo. We show that TIM-4(-/-) peritoneal macrophages and B-1 cells donot efficiently engulf apoptotic bodies in vitro, or clear apoptotic bodies in vivo. TIM-4-deficient mice have hyperactive T and B cells, elevated levels of serum Ig, and develop antibodies to double-stranded DNA. Taken together, we show that TIM-4 is critical for the clearance of apoptotic bodies in vivo, and that lack of TIM-4 results in aberrant persistence of apoptotic bodies leading to dysregulated lymphocyte activation and signs of systemic autoimmunity.