Schott Eckart, Bonasio Roberto, Ploegh Hidde L
Department of Pathology, Harvard Medical School, 200 Longwood Ave., Boston, MA 02115, USA.
J Exp Med. 2003 Oct 20;198(8):1213-24. doi: 10.1084/jem.20030918.
Natural killer cells gauge the absence of self class I MHC on susceptible target cells by means of inhibitory receptors such as members of the Ly49 family. To initiate killing by natural killer cells, a lack of inhibitory signals must be accompanied by the presence of activating ligands on the target cell. Although natural killer cell-mediated rejection of class I MHC-deficient bone marrow (BM) grafts is a matter of record, little is known about the targeting in vivo of specific cellular subsets by natural killer cells. We show here that development of class I MHC-negative thymocytes is delayed as a result of natural killer cell toxicity after grafting of a class I MHC-positive host with class I MHC-negative BM. Double positive thymocytes that persist in the presence of natural killer cells display an unusual T cell receptor-deficient phenotype, yet nevertheless give rise to single positive thymocytes and yield mature class I MHC-deficient lymphocytes that accumulate in the class I MHC-positive host. The resulting class I MHC-deficient CD8 T cells are functional and upon activation remain susceptible to natural killer cell toxicity in vivo. Reconstitution of class I MHC-deficient BM precursors with H2-K(b) by retroviral transduction fully restores normal thymic development.
自然杀伤细胞通过诸如Ly49家族成员等抑制性受体来检测易感靶细胞上是否缺乏自身I类主要组织相容性复合体（MHC）。要启动自然杀伤细胞的杀伤作用，抑制信号的缺失必须伴随着靶细胞上存在激活配体。尽管自然杀伤细胞介导的对I类MHC缺陷型骨髓（BM）移植物的排斥反应已有记录，但对于自然杀伤细胞在体内对特定细胞亚群的靶向作用知之甚少。我们在此表明，在将I类MHC阳性宿主与I类MHC阴性BM移植后，由于自然杀伤细胞的毒性作用，I类MHC阴性胸腺细胞的发育会延迟。在自然杀伤细胞存在的情况下持续存在的双阳性胸腺细胞表现出异常的T细胞受体缺陷表型，但仍能产生单阳性胸腺细胞，并产生在I类MHC阳性宿主中积累的成熟I类MHC缺陷型淋巴细胞。由此产生的I类MHC缺陷型CD8 T细胞具有功能，激活后在体内仍易受自然杀伤细胞毒性的影响。通过逆转录病毒转导用H2-K(b)重建I类MHC缺陷型BM前体可完全恢复正常的胸腺发育。
