Disease-specific T cell receptors maintain pathogenic T helper cell responses in postinfectious Lyme arthritis
Johannes Dirks, … , Florian Erhard, Henner Morbach
Johannes Dirks, … , Florian Erhard, Henner Morbach
Published July 4, 2024
Citation Information: J Clin Invest. 2024;134(17):e179391. https://doi.org/10.1172/JCI179391.
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Clinical Research and Public Health Autoimmunity Infectious disease Article has an altmetric score of 24

Disease-specific T cell receptors maintain pathogenic T helper cell responses in postinfectious Lyme arthritis

Abstract

BACKGROUND Antibiotic-Refractory Lyme Arthritis (ARLA) involves a complex interplay of T cell responses targeting Borrelia burgdorferi antigens progressing toward autoantigens by epitope spreading. However, the precise molecular mechanisms driving the pathogenic T cell response in ARLA remain unclear. Our aim was to elucidate the molecular program of disease-specific Th cells.METHODS Using flow cytometry, high-throughput T cell receptor (TCR) sequencing, and scRNA-Seq of CD4+ Th cells isolated from the joints of patients with ARLA living in Europe, we aimed to infer antigen specificity through unbiased analysis of TCR repertoire patterns, identifying surrogate markers for disease-specific TCRs, and connecting TCR specificity to transcriptional patterns.RESULTS PD-1hiHLA-DR+CD4+ effector T cells were clonally expanded within the inflamed joints and persisted throughout disease course. Among these cells, we identified a distinct TCR-β motif restricted to HLA-DRB1*11 or *13 alleles. These alleles, being underrepresented in patients with ARLA living in North America, were unexpectedly prevalent in our European cohort. The identified TCR-β motif served as surrogate marker for a convergent TCR response specific to ARLA, distinguishing it from other rheumatic diseases. In the scRNA-Seq data set, the TCR-β motif particularly mapped to peripheral T helper (TPH) cells displaying signs of sustained proliferation, continuous TCR signaling, and expressing CXCL13 and IFN-γ.CONCLUSION By inferring disease-specific TCRs from synovial T cells we identified a convergent TCR response in the joints of patients with ARLA that continuously fueled the expansion of TPH cells expressing a pathogenic cytokine effector program. The identified TCRs will aid in uncovering the major antigen targets of the maladaptive immune response.FUNDING Supported by the German Research Foundation (DFG) MO 2160/4-1; the Federal Ministry of Education and Research (BMBF; Advanced Clinician Scientist-Program INTERACT; 01EO2108) embedded in the Interdisciplinary Center for Clinical Research (IZKF) of the University Hospital Würzburg; the German Center for Infection Research (DZIF; Clinical Leave Program; TI07.001_007) and the Interdisciplinary Center for Clinical Research (IZKF) Würzburg (Clinician Scientist Program, Z-2/CSP-30).

Authors

Johannes Dirks, Jonas Fischer, Julia Klaussner, Christine Hofmann, Annette Holl-Wieden, Viktoria Buck, Christian Klemann, Hermann J. Girschick, Ignazio Caruana, Florian Erhard, Henner Morbach

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Figure 2

Convergent and ongoing T cell responses in the joints of patients with ARLA.

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Convergent and ongoing T cell responses in the joints of patients with A...
(A) Schematic work-flow illustrating the analysis process for identification of TCR similarities and clustering of TCRs into groups based on their probable specificity. (B) Network representation displaying TCR specificity groups enriched by GLIPH2 in SF PD-1hiHLA-DR+CD4+ T cells from 5 patients with ARLA with at least 1 HLA-DRB1*11 allele. Only specificity groups containing sequences from multiple patients are shown. Motifs are represented by small black circles, and corresponding CDR3-β sequences as colored circles; colors correspond to the sourcing individual sizes indicate the absolute abundancies of unique CDR3 amino acid (aa) sequences in all patients. (C) Tracking of occupied repertoire space within SF PD-1hiHLA-DR+CD4+ T cells using sequences containing CDR3 aa motifs from the specificity cluster at various time points in 3 patients. Each color corresponds to an unique CDR3 aa sequence. (D) Ratio comparison of the occupied repertoire space by sequences containing CDR3 aa motifs from the specificity cluster, defined in B, against the occupied repertoire space by CDR3 aa sequences in the ‘specificity cluster’ at time point 1 (as depicted in Supplemental Figure 2A).