Schols D, Vandekerckhove B, Jones D, Roncarolo M G
DNAX Research Institute, Human Immunology Department, Palo Alto, CA 94304-1104.
J Immunol. 1994 Mar 1;152(5):2198-206.
In this study we investigated the mechanism responsible for the unresponsiveness of thymus-reactive T cells obtained from severe combined immunodeficient (SCID) mice constructed with human fetal liver (FL) stem cells from donor A and an allogeneic human fetal thymus (FT) from donor B (A/B SCID-hu mice). These A/B SCID-hu mice have a human thymus containing B cells, macrophages, and dendritic cells from FL donor A but thymic epithelial cells from FT donor B. The repertoire of human T cells developing in this chimeric thymus is depleted of T cells specific for the HLA Ags of the FL donor, whereas T cells reactive against the HLA Ags expressed by the FT donor are still present. However, these thymocytes failed to proliferate and expressed low levels of the activation markers CD25, CD71, and HLA-DR after stimulation with the EBV-LCL of the FT donor in primary MLRs. This unresponsiveness could be completely reversed by IL-2. Restoration of T cell responsiveness was Ag specific and a unique property of IL-2. The T cells produced very low levels of IL-2 when stimulated with the HLA Ags of FT donor B, whereas they secreted normal levels of IL-2 after activation by third party alloantigens. Low IL-2 production was also observed at the clonal level. CD4+ T cell clones from A/B SCID-hu mice, specific for the HLA Ags of B, produced significantly less IL-2 and granulocyte macrophage-CSF than control CD4+ T cell clones. However, these T cell clones synthesized normal levels of IL-2 and granulocyte macrophage-CSF after stimulation with combinations of PMA/Calo or PMA/anti-CD3 mAb. Thus, T cells that differentiate in a chimeric thymus containing allogeneic host thymic epithelium are rendered tolerant to the HLA Ags expressed by the thymic epithelial cells. This tolerance results in the presence of T cells that do not proliferate properly after Ag-specific stimulation. This lack of proliferation is primarily related to their inability to produce sufficient levels of IL-2 and can be restored by exogenous IL-2.
在本研究中，我们探究了从用来自供体A的人胎肝（FL）干细胞和来自供体B的同种异体人胎胸腺（FT）构建的严重联合免疫缺陷（SCID）小鼠（A/B SCID-hu小鼠）中获得的胸腺反应性T细胞无反应性的机制。这些A/B SCID-hu小鼠具有一个人胸腺，其中包含来自FL供体A的B细胞、巨噬细胞和树突状细胞，但胸腺上皮细胞来自FT供体B。在这种嵌合胸腺中发育的人T细胞库中，针对FL供体HLA抗原的T细胞减少，而对FT供体表达的HLA抗原有反应的T细胞仍然存在。然而，在原发性混合淋巴细胞反应（MLR）中，用FT供体的EBV-LCL刺激后，这些胸腺细胞未能增殖，且活化标志物CD25、CD71和HLA-DR表达水平较低。这种无反应性可被白细胞介素-2（IL-2）完全逆转。T细胞反应性的恢复具有抗原特异性，是IL-2的独特特性。当用FT供体B的HLA抗原刺激时，T细胞产生的IL-2水平非常低，而在用第三方同种异体抗原激活后，它们分泌正常水平的IL-2。在克隆水平也观察到IL-2产生量低。来自A/B SCID-hu小鼠的针对B的HLA抗原的CD4+ T细胞克隆产生的IL-2和粒细胞巨噬细胞集落刺激因子（GM-CSF）明显少于对照CD4+ T细胞克隆。然而，在用佛波酯（PMA）/钙离子载体（Calo）或PMA/抗CD3单克隆抗体组合刺激后，这些T细胞克隆合成的IL-2和GM-CSF水平正常。因此，在含有同种异体宿主胸腺上皮的嵌合胸腺中分化的T细胞对胸腺上皮细胞表达的HLA抗原产生耐受。这种耐受导致T细胞在抗原特异性刺激后不能正常增殖。这种增殖缺乏主要与其产生足够水平IL-2的能力不足有关，并且可以通过外源性IL-2恢复。
