Rescue of cytotoxic function in the CD8alpha knockout mouse by removal of MHC class II.

Rescue of cytotoxic function in the CD8alpha knockout mouse by removal of MHC class II.
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通过去除 MHC II 类来挽救 CD8α 敲除小鼠的细胞毒功能。

DOI:
10.1002/eji.200737710
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发表时间:
2008
影响因子:
5.4
通讯作者:
Collins,EdwardJ
Collins,EdwardJ
中科院分区:
医学3区
文献类型:
--
作者:
Riddle,DavidS;Miller,PeterJ;Vincent,BenjaminG;Kepler,ThomasB;Maile,Rob;Frelinger,JeffreyA;Collins,EdwardJ

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CD 8在细胞溶解性T细胞(CTL)的活性中起重要作用。然而,CTL的发展是否需要CD 8尚未明确确定。CD 8 α敲除小鼠的细胞毒性活性很难诱导,并且仅针对同种异体MHC靶点进行了证明。细胞毒性的缺乏可能是由于在不存在CD 8的情况下CTL的谱系定型受损,或者在针对MHC II类(MHC II)上的CD 4 +T细胞(未受损)发育的选择期间竞争力降低。为了区分这些可能性,我们产生了双敲除小鼠(MHC II-/-CD 8 α-/-)。在MHC II-/-CD 8 α-/-小鼠中,发育中的MHC I类(MHC I)反应性胸腺细胞不能依赖于CD 8进行选择,但它们也不能被MHC II反应性胸腺细胞的有效选择所压倒。在这只小鼠中,产生了大量外周辅助受体双阴性(DN)和CD 4 +T细胞的异质群体。外周DN T细胞是功能齐全的CTL。它们对同种异体MHC和淋巴细胞性脉络丛脑膜炎病毒(LCMV)感染后对同基因MHC显示细胞溶解活性。来自LCMV感染小鼠的细胞在较低浓度下比其野生型CTL对应物结合更多的MHC I四聚体。这些结果明确地表明,CD 8不是胸腺细胞向CTL谱系定型所必需的。
CD8 plays an important role in the activity of cytolytic T cells (CTL). However, whether or not CD8 is required for the development of CTL has not been clearly determined. Cytotoxic activity in the CD8α knockout mouse is difficult to induce, and has only been demonstrated against allogenic MHC targets. The lack of cytotoxicity may result from impaired lineage commitment of CTL in the absence of CD8, or diminished competitiveness during selection against (unimpaired) development of CD4+T cells on MHC class II (MHC II). To differentiate between these possibilities, we have generated a double‐knockout mouse (MHC II–/–CD8α–/–). In MHC II–/–CD8α–/–mice, developing MHC class I (MHC I)‐reactive thymocytes cannot rely upon CD8 for selection, but they also cannot be overwhelmed by efficient selection of MHC II‐reactive thymocytes. In this mouse, a large, heterogeneous population of peripheral coreceptor double‐negative (DN) and CD4+T cells develops. Peripheral DN T cells are fully functional CTL. They display cytolytic activity against allogeneic MHC, and against syngeneic MHC following lymphocytic choriomeningitis virus (LCMV) infection. Cells from LCMV‐infected mice bind more MHC I tetramer at lower concentrations than their wild‐type CTL counterparts. These results demonstrate unequivocally that CD8 is not required for commitment of thymocytes to the CTL lineage.
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