Strong selection of a few dominant CD8 clones in a TLR7-dependent autoimmune mouse model

Abstract

Systemic lupus disease is characterized by the expansion of a self-reactive repertoire of B cells that, with the help of CD4 cells, generate IgG antibodies against common nuclear antigens. Meanwhile, the functional state and posible clonal selection of CD8 cells in lupus remain poorly defined. We previously described the activated but non-pathogenic phenotype of CD8+ T cells, some of which accumulate in the brain, in a model of systemic autoimmune disease triggered by increased copy number of the tlr7 gene (TLR7tg mice). Here we report, through the analysis of TCRβ sequences, that CD8+ cells from TLR7tg are strongly selected for a small number of clones, some of them reaching 30% of the repertoire, compared to less than 0.4% for a single top clone in wild type cells. High frequency clones are variable in sequence among individual TLR7tg mice and are distinct from top clones in WT, while cells from spleen and brain-resident cells from the same 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 are not selected by a tissue specific antigen. This kind of extreme clonal dominance and narrowing of the CD8+ T cell repertoire coud potentially impair anti-viral responses and should be considered as an additional detrimental feature of chronic autoimmune disease.