Morawski Peter A, Bolland Silvia
Laboratory of Immunogenetics, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852.
Laboratory of Immunogenetics, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852
Immunohorizons. 2019 Feb 11;3(2):61-70. doi: 10.4049/immunohorizons.1800082.
Systemic lupus is characterized by the expansion of a self-reactive repertoire of B cells and CD4 cells that together promote IgG Ab production against common nuclear Ags. Although several studies have suggested roles for CD8 T cells in lupus, the full contribution of these lymphocytes to disease remains undefined. In particular, few studies have examined TCR clonotypes of the CD8 pool in lupus. We previously described activated but nonpathogenic CD8 T cells in a mouse model of systemic autoimmune disease triggered by increased copy number of the gene (TLR7tg mice), in which some of these T cells accumulate in the brain. In this article, we report, through the analysis of TCRβ sequences, that CD8 cells from TLR7tg animals are strongly selected for a small number of clones, some of them reaching 30% of the repertoire, compared with less than 0.4% for the top clone in any wild type mice. High frequency clones are variable in sequence among individual TLR7tg mice and are distinct from top clones in the control animals, whereas CDR3 sequences of spleen and brain-resident T cells from the same TLR7tg animals have perfect concordance. These results suggest that top CD8 clones are selected in stochastic fashion in each animal but limit further diversification, and that brain-infiltrating CD8 cells in TLR7tg mice are not selected by a common tissue Ag. This kind of extreme clonal dominance and narrowing of the CD8 repertoire might impair anti-viral responses and should be considered as an additional detrimental feature of chronic autoimmune disease.
系统性红斑狼疮的特征是自身反应性B细胞和CD4细胞库的扩增，它们共同促进针对常见核抗原的IgG抗体产生。尽管多项研究表明CD8 T细胞在狼疮中发挥作用，但这些淋巴细胞对疾病的全部贡献仍不明确。特别是，很少有研究检测狼疮中CD8细胞库的TCR克隆型。我们之前在由基因拷贝数增加引发的系统性自身免疫疾病小鼠模型（TLR7转基因小鼠）中描述了活化但无致病性的CD8 T细胞，其中一些T细胞在大脑中积聚。在本文中，我们通过对TCRβ序列的分析报告称，与任何野生型小鼠中顶级克隆不到0.4%相比，TLR7转基因动物的CD8细胞强烈选择少数克隆，其中一些克隆占细胞库的30%。高频克隆在个体TLR7转基因小鼠中的序列各不相同，且与对照动物中的顶级克隆不同，而来自同一TLR7转基因动物的脾脏和驻留在大脑中的T细胞的CDR3序列完全一致。这些结果表明，顶级CD8克隆在每只动物中以随机方式被选择，但限制了进一步的多样化，并且TLR7转基因小鼠中浸润大脑的CD8细胞不是由共同的组织抗原选择的。这种极端的克隆优势和CD8细胞库的狭窄可能会损害抗病毒反应，应被视为慢性自身免疫疾病的另一个有害特征。
