Identifizierung von krankheitsrelevanten T Zell Klonen und arthritogenen Antigenen bei ankylosierender Spondylitis
Zusammenfassung der Projektergebnisse
Ankylosing spondylitis (AS) is subform of spondyloarthritis (SpA). It is a chronic inflammatory disease of high prevalence with unclear pathogenesis and may affect both the axial skeleton and peripheral joints. A remarkable feature of SpA is that the majority of Caucasian patients share the HLA class I allele HLA-B*27:05, i.e. a single allele amongst more than twenty thousand possible alleles. Since class I HLA molecules present antigenic peptides to CD8+ (cytotoxic) T cells, this suggests that CD8+ T cells in SpA recognize arthritogenic HLA/peptide complexes and are thus main drivers of the disease. They recognize HLA/peptide complexes using their T cell receptors (TCR), which consist (like antibodies) of hypervariable alpha- and beta-chains. However, alternative models for the pathogenesis of SpA have been proposed, which are based on formation of denatured HLA molecules, which would initiate innate immune reactions. In these models, recognition of specific HLA/peptide complexes is not relevant. Here we set out to investigate properties of CD8+ T cells that showed signs of previous contact with specific antigens. To this end, we isolated CD8+ T cells from synovial fluid of 17 HLA-B27 positive patients and controls and analyzed the TCR alpha- and beta-chains of 116,593 single cells. We found that many T cells that belonged to expanded populations, had highly homologous Variable regions, which are known to interact predominantly with HLA molecules. Further, we could show that the hypervariable regions of the TCR chains, which are known to interact predominantly with antigenic peptides, are also highly homologous. Both observations strongly indicate that these T cells may recognize the same HLA molecules (i.e. HLA-B27:05) that had similar antigenic peptides bound. Moreover, analysis of whole transcriptomes of single cells showed that many of the expanded T cell clonotypes showed signs of apoptosis or had a so called "tissue resident memory (TRM)" phenotype, which is known to be formed after sustained contact with specific antigens. That is, naïve T cells become effector T cells upon contact with antigens, the effector T cells then divide rapidly and are deleted by apoptosis after having successfully defeated the antigens. However, a small fraction will adopt the TRM phenotype and will stay in the tissue as a guard to fight the antigen again as soon as it returns. Our observation of expanded T cell clones with TRM features therefore also strongly argues for contact with specific antigens. Taken together, several independent lines of evidence suggest that CD8+ T cells in SpA recognize specific antigens presented by HLA-B27:05. These data shed light on the pathogenesis of SpA and may guide further experiments to improve diagnostics and therapy of SpA.
