Roberts J L, Volkman D J, Buckley R H
Department of Pediatrics, Duke University School of Medicine, Durham, NC 27710.
J Immunol. 1989 Sep 1;143(5):1575-9.
The choice of class II MHC determinants that serve as self-recognition elements for murine CD4+ T cells is thought to be determined by the environment in which T cells mature rather than their genotype. Patients with severe combined immunodeficiency (SCID) reconstituted with T cell depleted haploidentical parental stem cells provide an excellent model for studying this phenomenon in humans. After engraftment, the T cells that develop in these infants are all of donor origin. We sought to determine whether the successful immune reconstitution observed in two such SCID chimeras involved modification of the MHC restriction of Ag recognition by the genetically donor T cells as they matured to become competent T cells in the infants' microenvironment. A tetanus toxoid (TT)-specific T cell line and TT-specific T cell clones were established from the blood of two reconstituted SCID patients and from their maternal donors. T cell responsiveness was determined by [3H]thymidine incorporation after TT presentation by EBV-transformed B cell lines (EBV-B) from various donors. The TT-specific T cell line from patient 1 proliferated when presented Ag by patient, maternal donor, and paternal APC. A CD4+ donor origin clone that proliferated when presented TT by patient and paternal EBV-B, but not by maternal donor EBV-B, was isolated from each patient. TT recognition by these clones was shown to be restricted by the HLA DR determinant shared by patient and father, but not present in the donor. Four TT-specific clones isolated from maternal donors failed to proliferate when presented TT by the appropriate paternal EBV-B. These studies demonstrate that, in these human SCID bone marrow chimeras, engrafted donor-origin stem cells maturing to competent T cells in the recipient microenvironment are capable of utilizing recipient HLA determinants as restriction elements for Ag recognition. This suggests that human, as well as murine, MHC restriction patterns for Ag recognition by CD4+ T cells are environmentally determined.
作为小鼠CD4 + T细胞自我识别元件的II类MHC决定簇的选择被认为是由T细胞成熟的环境而非其基因型决定的。用去除T细胞的单倍体亲代干细胞重建的严重联合免疫缺陷（SCID）患者为研究人类中的这一现象提供了一个极好的模型。植入后，这些婴儿体内发育的T细胞均来自供体。我们试图确定在两个这样的SCID嵌合体中观察到的成功免疫重建是否涉及基因供体T细胞在婴儿微环境中成熟为有功能的T细胞时对Ag识别的MHC限制的改变。从两名重建的SCID患者及其母亲供体的血液中建立了破伤风类毒素（TT）特异性T细胞系和TT特异性T细胞克隆。通过来自不同供体的EBV转化B细胞系（EBV - B）呈递TT后，通过[3H]胸苷掺入来确定T细胞反应性。患者1的TT特异性T细胞系在由患者、母亲供体和父亲的APC呈递Ag时增殖。从每个患者中分离出一个CD4 +供体来源的克隆，当由患者和父亲的EBV - B呈递TT时该克隆增殖，但由母亲供体的EBV - B呈递时不增殖。这些克隆对TT的识别显示受患者和父亲共有的HLA DR决定簇限制，但供体中不存在该决定簇。从母亲供体分离出的四个TT特异性克隆在由合适的父亲EBV - B呈递TT时未增殖。这些研究表明，在这些人类SCID骨髓嵌合体中，植入的供体来源干细胞在受体微环境中成熟为有功能的T细胞时能够利用受体HLA决定簇作为Ag识别的限制元件。这表明人类以及小鼠中CD4 + T细胞对Ag识别的MHC限制模式是由环境决定的。
