Conserved TCR β chain usage in reactive arthritis; evidence for selection by a putative HLA‐B27‐associated autoantigen

Abstract

Previous work suggested that expanded CD8+ T-cell clones in the synovial fluid (SF) of HLA-B27+ patients with reactive arthritis (ReA) preferentially use the T-cell receptor variable region (TCRBV) 1, similar CDR3 sequences, and joining region (BJ) 2S3. To determine the range of conservation and disease-specificity of CDR3-sequences, we analyzed the TCRBV1-J2S3 repertoire from 33 healthy HLA-B27+ individuals, patients with various types of spondyloarthropathies (SpA), and with rheumatoid arthritis (RA) by CDR3-spectratyping. After collection and database submission of all available TCRB-CDR3 from HLA-B27-restricted or SpA-derived T cells, we systematically screened the entire human sequence database for sequences similar to the B27/SpA-related CDR3. Spectratyping revealed expanded T cell clones using conserved TCRBV1J2S3 in the SF from 5/6 of the patients with acute ReA but not among the controls. In database searches, 50 HLA-B27 or SpA-related CDR3-sequences generated similar clusters of matched sequences, and matched reciprocally. Identical or closely related sequences were identified in 15 different individuals and a canonical ReA-associated TCRB was defined [BV1-CASSVG(V/I/L)(Y/F)STDTQYF-J2S3]. All but one patient-derived conserved sequences originated from acute stage ReA-patients, and were not present among approximately 3800 other human TCRB sequences in the database. Five of the conserved sequences originated from T cell clones that recognized uninfected cells in an HLA-B27-restricted fashion, implying a role of HLA-B27-restricted CD8+ T cells specific for a ubiquitous self- or cross-reactive microbial determinant in the early phase of ReA. Related sequences were independently identified in four different laboratories. The consensus TCRB motif could be a helpful diagnostic marker in HLA-B27-associated 'undifferentiated arthritis'.

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

“…To test this, we collected CD4+ and CD8+ T cells from SJF in 2 AS patients from our cohort, sequenced their TCR repertoires and performed Motif Analysis to identify AS specific motifs. Moreover, using another independent AS cohort [63], we validated AS specific motifs from both our AS cohort and previous studies [64,65] (Fig. 6a).…”

“…Next, using another AS validation cohort [63], we investigated a common T cell response using shared full length CDR3s and AS specific CDR3 motifs from our study and previous study [64,65] (Fig. 6j).…”

Detecting T cell receptors involved in immune responses from single repertoire snapshots

“…Although most predicted TCRs were patient-specific, 2 clonotypes were independently found in all 3 HLA-B27 + patients but not in the HLA-B27 − patient. These 2 clonotypes exactly coincide with previously reported public clonotypes in a population of HLA-B27 + patients with AS [7, 8] and were also found in synovial fluid spectratyping of patients with AS and reactive arthritis [22, 23]. The independent identification of these sequences by ALICE demonstrates the relevance of its predictions, as well as suggests that these public clonotypes actively participate in the immune response in inflamed joints.…”

Single-cell sequencing reveals clonal expansions of pro-inflammatory synovial CD8 T cells expressing tissue-homing receptors in psoriatic arthritis

“…Costello and colleagues identified an average of 32 private T-cell receptor (TCR) beta-chain clonal expansions unique to individual patients and primarily confined to synovial fluid. While they found evidence supporting antigen-driven selection, with differing nucleic acid sequences encoding common amino acid sequences, they did not see evidence of shared or public repertoires between different patients, as previously described for HLA-B27-associated spondyloarthritis 5 . Leucocytes are recruited to the synovium and synovial fluid through chemokine gradients, with bulk synovial fluid cell pellet RNA showing increased expression of the CXCR3 gene and synovial fluid showing increased expression of one of its protein ligands CCL10 6 .…”