Fukuzawa M, Via C S, Shearer G M
Immunology Branch, National Cancer Institute, Bethesda, MD 20892.
J Immunol. 1988 Jul 15;141(2):430-9.
Our study investigates the effect of a prior graft-vs-host (GVH) reaction on the subsequent ability of irradiated, bone marrow-re-populated mice to develop T cell function. The results indicate that such GVH-bone marrow transplanted (BMT) mice do not generate CTL responses to trinitrophenyl-modified syngeneic cells (TNP-self), but do generate strong CTL activity to H-2 alloantigens. This selective deficiency in TNP-self CTL response potential appeared as early as 10 days after GVH, and required both L3T4+ and Lyt-2+ donor T cells. The in vitro addition of either soluble Th factors or L3T4-enriched spleen cells from normal mice circumvented the defect in the TNP-self response in GVH-BMT mice. These results indicate that T effector function was not defective, and instead suggest a Th defect. Cell depletion and antibody-blocking, as well as IL-2 production experiments, indicate that the Th defect was selective for L3T4+ Th population and not for Lyt-2+ Th population. This defect in L3T4 Th function is not accounted for by the approximate twofold reduction in L3T4 cell numbers in GVH-BMT mice, because IL-2 production and CTL generation to L3T4-dependent Ag were at least eightfold below control levels. Rather, defective L3T4 Th function appears to be the consequence of a GVH-induced defect in thymic maturation because the defect was corrected in vivo by a neonatal parental thymus graft before irradiation and bone marrow transplantation. This system may be useful for elucidating the role of the thymus in the maturation of Th cells. Our findings raise the possibility that impaired development of T cell function occurring in marrow grafted patients who have undergone a GVH reaction could be partly due to a GVH-induced thymic defect.
我们的研究调查了先前的移植物抗宿主（GVH）反应对经辐射、骨髓再填充小鼠随后发展T细胞功能能力的影响。结果表明，此类GVH-骨髓移植（BMT）小鼠对三硝基苯基修饰的同基因细胞（TNP-自身）不产生细胞毒性T淋巴细胞（CTL）反应，但对H-2同种异体抗原产生强烈的CTL活性。TNP-自身CTL反应潜能的这种选择性缺陷早在GVH后10天就出现了，并且需要L3T4+和Lyt-2+供体T细胞。体外添加可溶性Th因子或来自正常小鼠的富含L3T4的脾细胞可克服GVH-BMT小鼠TNP-自身反应的缺陷。这些结果表明T效应功能没有缺陷，反而提示存在Th缺陷。细胞清除和抗体阻断以及白细胞介素-2产生实验表明，Th缺陷对L3T4+ Th群体具有选择性，而对Lyt-2+ Th群体没有选择性。GVH-BMT小鼠中L3T4细胞数量大约减少两倍并不能解释L3T4 Th功能的这种缺陷，因为白细胞介素-2的产生以及对L3T4依赖性抗原的CTL生成比对照水平至少低八倍。相反，有缺陷的L3T4 Th功能似乎是GVH诱导的胸腺成熟缺陷的结果，因为在辐射和骨髓移植前通过新生亲本胸腺移植在体内纠正了该缺陷。该系统可能有助于阐明胸腺在Th细胞成熟中的作用。我们的发现增加了这样一种可能性，即在经历GVH反应的骨髓移植患者中发生的T细胞功能发育受损可能部分归因于GVH诱导的胸腺缺陷。
