TCR repertoire and CDR3 motif analyses depict the role of αβ T cells in Ankylosing spondylitis

Abstract

BackgroundAnkylosing spondylitis (AS) is a chronic inflammatory disease with worldwide high prevalence. Although AS is strongly associated with HLA-B27 MHC-I antigen presentation, the role played by αβ T cells in AS remains elusive.MethodsUtilizing TCRβ repertoire sequencing and bioinformatics tools developed in house, we analyzed overall TCR repertoire structures and antigen-recognizing CDR3 motifs in AS patients with different disease activities.FindingsWe found that disease progression is associated with both CD4+ and CD8+ T cell oligo-clonal expansion, which suggests that αβ T cell activation may mediate AS disease progression. By developing a bioinformatics platform to dissect antigen-specific responses, we discovered a cell population consisting of both CD4+ and CD8+ T cells expressing identical TCRs, herein termed CD4/8 T cells. CD4/8 clonotypes were highly enriched in the spondyloarthritic joint fluid of patients, and their expansion correlated with the activity of disease.InterpretationThese results provide evidence on the T cell clone side to reveal the potential role of CD4/8 T cells in the etiology of AS development.

Perspectives on the Genetic Associations of Ankylosing Spondylitis

“…Evidence for antigen-driven specific immune responses in the HLA-B27 associated arthropathies, is not new (90, 91) but the development of high throughput sequencing to assess the Tcell receptor repertoire has seen a recent resurgence of interest. Of particular interest, TCR binding motifs from some patients with AS show similarities with those identified previously in individuals with reactive arthritis (92)(93)(94)(95). There is also evidence of a significant increase in CD8+ T-cell clonotypes specific for the Epstein-Barr and cytomegalovirus (92).…”

TCR repertoire characteristics predict clinical response to adoptive CTL therapy against nasopharyngeal carcinoma

“… 36 , 37 When applied to TCR repertoire analysis, Motif Analysis compellingly enhances the accuracy in organizing TCRs based on shared antigen specificities, eventually leading to more reliable frequency quantification of antigen-specific T cells. 20 , 36 To perform Motif Analysis, we pooled all CDR3 clonotypes together from all LTS, and the unique CDR3 list was generated by removing the duplicates. The 2mer, 3mer, and 4mer connected amino acid sequences derived from the top 10% unique CDR3 clonotypes constituted the initial motif pools.…”

“…Using a certain CDR3 set as an anchor, we screened the entire TCR repertoire to distinguish TCRs with the same epitope specificities even without apparent global sequence similarity. 19 , 20 Here, we applied these tools to assess repertoire features of EBV-expanded CTLs produced during clinical trial NCT00690872, hypothesizing that certain TCR repertoire features might inform the prediction of responsiveness to CTL immunotherapy in patients with NPC.…”

Juvenile Spondyloarthritis: What More Do We Know About HLA-B27, Enthesitis, and New Bone Formation?

“…Current studies have employed high-dimensional technologies to interrogate the specificity of the B27-restricted T cell responses, and to define putative autoantigens responsible for these responses. Using next-generation sequencing-aided high-throughput T cell receptor (TCR) repertoire analysis (Rep-seq), a recent study demonstrated a positive association between disease activity and the oligoclonal expansion of not just CD8 + but also CD45RA + effector memory CD4 + (T EMRA ; CD45RA + CD45RO − CD62L − ) T cells in the inflamed joints of HLA-B27 + AS patients ( 84 ). It also identified common complementarity determining region 3 (CDR3) motifs unique to the pathological CD4 + and CD8 + T cells.…”