Perkins D L, Listman J A, Marshak-Rothstein A, Kozlow W, Kelley V R, Finn P W, Rimm I J
Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
J Immunol. 1996 Jun 15;156(12):4961-8.
The lpr mutation, a disruption of the fas gene, induces spontaneous autoimmunity characterized by high titers of autoantibodies, lymphadenopathy, autoreactive T cells, and early mortality. The mechanism of autoimmunity, however, remains unknown. The driving force for disease could result from the T cell recognition of autoantigen or, alternatively, an intrinsic T cell defect that promotes autoreactivity. We investigated the role of antigen-TCR interaction in the pathogenesis of lpr autoimmunity by transferring the DO-11.10 TCR beta-chain transgene (Vbeta8.2-Dbeta1.1-Jbeta1.1) to the MRL-lpr/lpr background producing the MRL-lprbeta strain. Our results show that the MRL-lpr beta transgenic strain has increased survival, lower titers of autoantibodies, and decreased lymphadenopathy compared with nontransgenic littermates. These beneficial effects were associated with decreased expansion of CD4+ T cells expressing memory phenotypes (CD44+, CD45RB-, and LECAM-) in the transgenic compared with nontransgenic strains. A role for impaired recognition of autoantigen by T cells expressing the TCR transgene was suggested by comparing the phenotypes of Vbeta8.2+ (transgene+) vs Vbeta8.2- (transgene-) CD4+ T cells within the transgenic mice. These experiments show that Vbeta8.2- T cells, which express endogenously rearranged TCR, are the major contributors to the expansion of memory T cells in the transgenic mice. In contrast, T cells with memory phenotypes expand similarly in both the Vbeta8.2+ and Vbeta8.2- subsets of nontransgenic mice. Based on these results, we hypothesize that TCR recognition of autoantigen is a major contributor to autoimmunity in lpr mice and that T cells expressing a memory phenotype are perpetrators of this process.
lpr突变是fas基因的一种破坏，可诱导以高滴度自身抗体、淋巴结病、自身反应性T细胞和早期死亡为特征的自发性自身免疫。然而，自身免疫的机制仍然未知。疾病的驱动力可能源于T细胞对自身抗原的识别，或者是促进自身反应性的内在T细胞缺陷。我们通过将DO-11.10 TCRβ链转基因（Vβ8.2-Dβ1.1-Jβ1.1）转移到MRL-lpr/lpr背景中产生MRL-lprβ品系，研究了抗原-TCR相互作用在lpr自身免疫发病机制中的作用。我们的结果表明，与非转基因同窝小鼠相比，MRL-lprβ转基因品系的存活率提高，自身抗体滴度降低，淋巴结病减轻。这些有益效果与转基因品系中表达记忆表型（CD44+、CD45RB-和LECAM-）的CD4+T细胞的扩增减少有关。通过比较转基因小鼠中Vβ8.2+（转基因+）与Vβ8.2-（转基因-）CD4+T细胞的表型，提示表达转基因TCR的T细胞对自身抗原的识别受损起到了作用。这些实验表明，表达内源性重排TCR的Vβ8.2-T细胞是转基因小鼠中记忆T细胞扩增的主要贡献者。相比之下，具有记忆表型的T细胞在非转基因小鼠的Vβ8.2+和Vβ8.2-亚群中扩增情况相似。基于这些结果，我们假设TCR对自身抗原的识别是lpr小鼠自身免疫的主要促成因素，并且表达记忆表型的T细胞是这一过程的实施者。
