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

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 6

ARLA-specific T cell clones map to the TPH cluster and show signs of TCR-driven activation.

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ARLA-specific T cell clones map to the TPH cluster and show signs of TCR...
(A) UMAP representations of cell clustering via scRNA-Seq analysis of SF CD4+ T cells from 3 ARLA patients (from Figure 5A). In the center, cells with viral TCR motifs are highlighted, while on the right those with the ARLA motifs (CDR1-β and CDR3-β motifs) are highlighted. (B) Relative distribution of cells within each cluster, categorized by color as depicted in A, considering all cells or cells containing either viral or ARLA TCR motifs. Fisher’s exact test between indicated groups; ****P < 0.0001. (C) Normalized enrichment scores (NES) from Gene Set Enrichment Analysis (GSEA) analysis using Reactome pathways with differentially expressed genes between TPH cells (cluster 0 and 3) with either viral or ARLA TCR motifs. Pathways are ranked based on their NES, with circle size corresponding to negative log10 (adjusted P value). Red circles represent pathways with an adjusted P value < 0.05. The significantly enriched pathways are identified by name. (D) Genes associated with TCR signaling-related GSEA pathways were used as input for the AddModuleScore function from Seurat. Resulting scores per cell are plotted and compared between TPH cells containing no motifs, viral or ARLA TCR motifs. (E) Expression of selected activation and effector genes in the same groups as in D. 1-way ANOVA with Tukey’s multiple comparisons test; P values < 0.1 are shown, *P < 0.05, **P < 0.01, ***P < 0.001.