Blazar B R, Taylor P A, Panoskaltsis-Mortari A, Barrett T A, Bluestone J A, Vallera D A
Department of Pediatrics, University of Minnesota Hospital, Minneapolis 55455, USA.
Blood. 1996 Jan 15;87(2):827-37.
Although T-cell receptor (TCR) alpha/beta expressing cells have a well-known role in graft-versus-host disease (GVHD) generation, the role of TCR gamma/delta expressing cells in this process has remained unclear. To elucidate the potential function of TCR gamma/delta cells in GVHD, we have used transgenic (Tg) H-2d mice (termed G8) that express gamma/delta heterodimers on a high proportion of peripheral T cells. In vitro, G8 Tg gamma/delta T cells proliferate to and kill C57BL/6 (B6) (H-2b) which express gene products (T10b and T22b) from the nonclassical major histocompatibility complex (MHC) class Ib H-2T region. The infusion of G8 Tg (H-2Td) TCR gamma/delta cells into lethally irradiated [900 cGy total body irradiation (TBI)] B6 (H-2b) mice resulted in the generation of lethal GVHD characterized histologically by destruction of the spleen, liver, lung, and colon. Lethal GVHD was prevented by the injection of anti-TCR gamma/delta monoclonal antibodies. Immunohistochemical analysis of B6 recipients post-bone marrow transplantation (BMT) confirmed that G8 Tg TCR gamma/delta cells infiltrated GVHD target tissues (skin, liver, colon, and lung) and were absent in recipients treated with anti-TCR gamma/delta monoclonal antibodies (MoAbs) but not anti-CD4 plus anti-CD8 MoAbs. In contrast, injection of TCR gamma/delta+ cells into irradiated (900 cGy TBI) B6.A-TIaa BoyEg mice that do not express either T10b or T22b did not induce lethal GVHD. Similarly, in a different GVHD system in which sublethal irradiation without bone marrow (BM) rescue was used, B6 but not B6.A-TIaa/BoyEg mice were found to be susceptible to TCR gamma delta+ cell mediated GVHD-induced lethality characterized by an aplasia syndrome. These results demonstrate that TCR gamma/delta cells have the capacity to cause acute lethal GVHD in mice and suggest that nonclassical MHC class Ib gene products expressed on GVHD target organs are responsible for G8 Tg TCR gamma/delta+ cell mediated lethality.
尽管表达T细胞受体（TCR）α/β的细胞在移植物抗宿主病（GVHD）的发生中具有众所周知的作用，但表达TCRγ/δ的细胞在此过程中的作用仍不清楚。为了阐明TCRγ/δ细胞在GVHD中的潜在功能，我们使用了转基因（Tg）H-2d小鼠（称为G8），其在外周T细胞的高比例上表达γ/δ异二聚体。在体外，G8 Tgγ/δ T细胞增殖并杀死表达来自非经典主要组织相容性复合体（MHC）I类b H-2T区域的基因产物（T10b和T22b）的C57BL/6（B6）（H-2b）细胞。将G8 Tg（H-2Td）TCRγ/δ细胞输注到经致死性照射[900 cGy全身照射（TBI）]的B6（H-2b）小鼠中，导致产生致命的GVHD，组织学特征为脾脏、肝脏、肺和结肠的破坏。注射抗TCRγ/δ单克隆抗体可预防致命的GVHD。对骨髓移植（BMT）后的B6受体进行免疫组织化学分析证实，G8 Tg TCRγ/δ细胞浸润到GVHD靶组织（皮肤、肝脏、结肠和肺）中，在用抗TCRγ/δ单克隆抗体（MoAbs）而非抗CD4加抗CD8 MoAbs治疗的受体中不存在。相反，将TCRγ/δ +细胞注射到不表达T10b或T22b的经照射（900 cGy TBI）的B6.A-TIaa BoyEg小鼠中不会诱导致命的GVHD。同样，在使用无骨髓（BM）救援的亚致死照射的不同GVHD系统中，发现B6小鼠而非B6.A-TIaa/BoyEg小鼠易受TCRγδ +细胞介导的以发育不全综合征为特征的GVHD诱导的致死性影响。这些结果表明，TCRγ/δ细胞有能力在小鼠中引起急性致命性GVHD，并表明在GVHD靶器官上表达的非经典MHC I类b基因产物是G8 Tg TCRγ/δ +细胞介导的致死性的原因。
