Reder A T, Lascola C D, Flanders S A, Maimone D, Jensen M A, Skias D D, Lancki D W
Department of Neurology, University of Chicago, Illinois 60637.
Transplantation. 1993 Aug;56(2):393-9. doi: 10.1097/00007890-199308000-00028.
The brain is "immunologically privileged," in part because class I and II MHC antigens are not normally present on glia or neurons. However, under certain conditions such as transplantation, glial cells express MHC proteins at levels sufficient for glia to become targets of immune responses. Cultured astrocytes expressing very low levels of MHC class I protein are killed efficiently by MHC class I antigen-specific CTL. Mouse brain allografts, however, are rejected by CD4+ T cells that are likely to be class II MHC-specific. The level of expression of MHC class II antigen needed to trigger specific killing of astrocytes by CD4+ T cells, independent of exogenous antigen, has not been studied. We examined the role of glial class II MHC in the lysis of cultured neonatal mouse astrocytes by an alloreactive murine CD4+ CTL alone. IFN-gamma induced functionally relevant increases in MHC class II antigen on target cells. Astrocytes were lysed by the CD4+ clone only when class II MHC antigens reached levels readily detectable by flow cytometry. MHC class II expression and lysis increased when astrocytes were coincubated with IFN-gamma and TNF-alpha. Conversely, lysis decreased when class II expression was downregulated by IFN-alpha/beta or dbcAMP. Cytolysis by CD4+ clones was blocked by antibodies to CD4 and LFA-1 on T cells, and to ICAM-1 and class II molecules on astrocytes. The role of LFA-1 in CD4+ cell-mediated lysis was greater than that of LFA-1/ICAM-1 in CD8+ T cell-mediated lysis. CD4+ cells may lyse activated astrocytes when the immune privilege of the brain is compromised as in transplantation, tumors, and inflammatory diseases.
大脑具有“免疫特权”，部分原因是I类和II类主要组织相容性复合体（MHC）抗原通常不在神经胶质细胞或神经元上表达。然而，在某些情况下，如移植时，神经胶质细胞会表达足够水平的MHC蛋白，从而使神经胶质细胞成为免疫反应的靶标。表达极低水平I类MHC蛋白的培养星形胶质细胞会被I类MHC抗原特异性细胞毒性T淋巴细胞（CTL）有效杀伤。然而，小鼠脑同种异体移植会被可能针对II类MHC的CD4 + T细胞排斥。触发CD4 + T细胞特异性杀伤星形胶质细胞所需的II类MHC抗原表达水平（不依赖外源性抗原）尚未得到研究。我们单独研究了同种反应性小鼠CD4 + CTL对培养的新生小鼠星形胶质细胞裂解中神经胶质II类MHC的作用。γ干扰素诱导靶细胞上功能相关的II类MHC抗原增加。只有当II类MHC抗原达到流式细胞术易于检测的水平时，星形胶质细胞才会被CD4 +克隆裂解。当星形胶质细胞与γ干扰素和肿瘤坏死因子-α共同孵育时，II类MHC表达和裂解增加。相反，当II类表达被α/β干扰素或二丁酰环磷腺苷（dbcAMP）下调时，裂解减少。CD4 +克隆的细胞溶解作用被T细胞上的CD4和淋巴细胞功能相关抗原-１（LFA-1）抗体以及星形胶质细胞上的细胞间黏附分子-1（ICAM-1）和II类分子抗体所阻断。LFA-1在CD4 +细胞介导的裂解中的作用大于LFA-1/ICAM-1在CD8 + T细胞介导的裂解中的作用。当大脑的免疫特权在移植、肿瘤和炎症性疾病中受到损害时，CD4 +细胞可能会裂解活化星形胶质细胞。
