CD4+ and CD8+ clonal T cell expansions indicate a role of antigens in ankylosing spondylitis; a study in HLA-B27+ monozygotic twins

Abstract

Ankylosing spondylitis (AS) is a complex genetic disease in which both MHC and non-MHC genes determine disease susceptibility. To determine whether the T cell repertoires of individuals with AS show signs of increased stimulation by exogenous antigens, CD4+ and CD8+ T cell subsets of five monozygotic HLA-B27+ twins (two concordant and three discordant for AS) and CD8+ T cell repertoires of three healthy HLA-B27+ individuals were characterized by TCR beta-chain (TCRB) CDR3 size spectratyping. Selected TCRB-CDR3 spectra were further analysed by BJ-segment analysis and TCRB-CDR3 from expanded T cell clones were sequenced. In an analysis of all data (519/598 possible TCRB-CDR3 spectra), AS was associated with increased T cell oligoclonality in both CD8+ (P = 0.0001) and CD4+ (P = 0.033) T cell subsets. This was also evident when data were compared between individual twins. Nucleotide sequence analysis of expanded CD8+ or CD4+ T cell clones did not show selection for particular TCRB-CDR3 amino acid sequence motifs but displayed sequence homologies with published sequences from intra-epithelial lymphocytes or synovial T cells from rheumatoid arthritis patients. Together, these results provide support for the hypothesis that responses to T cell-stimulating exogenous or endogenous antigens are involved in the induction and/or maintenance of AS.

Fig. 1

Categorization of TCRB-CDR3 spectra. All samples are from twin pair IC. TCRBV9 and TCRBV12 CDR3 spectra show a Gaussian distribution of band intensities indicating polyclonal T cell populations (category i). TCRBV13.1 CDR3 spectra show a non-Gaussian distribution of band intensities indicating oligoclonal T cell populations in the absence of clearly dominating bands in CD8⁺ T cells of twin B (category ii) and a restricted spectrum with one dominant band in CD8⁺ T cells of twin A (category iii). TCRBV8 spectra in peripheral blood mononuclear cells (PBMC) and the CD8⁺ subset of twin B are restricted and dominated by two expanded bands (category iii).