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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

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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 3

A combined CDR1β / CDR3β surrogate marker defines a common disease-associated TCRs motif.

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A combined CDR1β / CDR3β surrogate marker defines a common disease-assoc...
(A) The distribution of TRBV-TRBJ gene segment pairings is depicted in circos plots, showing unique TCRβ chain sequences derived from SF PD-1hiHLA-DR+CD4+ T cells collected from 5 ARLA patients. The upper circle delineates sequences belonging to the ‘specificity cluster,’ as illustrated in Figure 2A, while the lower circle represents the remaining sequences. The TRBV7-2.TRBJ2-7 and TRBV18.TRBJ2-7 pairing are highlighted in red and blue, respectively. (B) Sequence plots depicting the amino acid sequences in CDR1-3β derived from sequences within the specificity cluster. For the generation of sequence plots, TCR sequences were filtered to include the most abundant length of each CDR. Potential surrogate markers, such as GH in CDR1-β (CDR-1β motif) and SL/SV in CDR3-β (CDR3β motif), are outlined in red. (C) The frequencies of the indicated surrogate markers are compared between sequences within and outside the specificity cluster; P values determined by multiple paired t tests are adjusted for multiple testing by Holm-Šídák method; *P < 0.05, ***P < 0.001 Bars indicate mean ± SD. (D) Alluvial plot of TRAV-TRAJ-TRBV-TRBJ combinations (determined by paired TCR-α/β–sequencing of CD4+ SF T cells from 3 patients with ARLA) in unique clones containing motifs from the specificity cluster in the CDR3-β. Alluvials from clones with the CDR3-β motif (SL/SV at IMGT position 111/112 in CDR3-β) are highlighted in coral. (E) Frequency of clones with TRAV23/DV6 gene segment usage within all clones or within subsets filtered for the indicated properties of the TCR-β chain. The number of clones in each subset is indicated at each bar. Circles represent individual patients, error bars indicate SD. Significances were calculated by 1-way ANOVA and multiple comparisons (to all clones) corrected with Dunnetts formula; *P < 0.05, **P < 0.01.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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