Compartmentalization and persistence of dominant (regulatory) T cell clones indicates antigen skewing in juvenile idiopathic arthritis

Abstract

Autoimmune inflammation is characterized by tissue infiltration and expansion of antigen-specific T cells. Although this inflammation is often limited to specific target tissues, it remains yet to be explored whether distinct affected sites are infiltrated with the same, persistent T cell clones. Here we performed CyTOF analysis and T cell receptor (TCR) sequencing to study immune cell composition and (hyper-)expansion of circulating and joint-derived Tregs and non-Tregs in Juvenile Idiopathic Arthritis (JIA). We studied different joints affected at the same time, as well as over the course of relapsing-remitting disease. We found that the composition and functional characteristics of immune infiltrates are strikingly similar between joints within one patient, and observed a strong overlap between dominant T cell clones, especially Treg, of which some could also be detected in circulation and persisted over the course of relapsing remitting disease. Moreover, these T cell clones were characterized by a high degree of sequence similarity, indicating the presence of TCR clusters responding to the same antigens. These data suggest that in localized autoimmune disease there is auto-antigen driven expansion of both Teffector and Treg clones, that are highly persistent and are (re)circulating. These dominant clones might represent interesting therapeutic targets.

Integration of genetic and epigenetic data pinpoints autoimmune specific remodelling of enhancer landscape in CD4+ T cells

“…This may reflect the distinct roles that Tregs plays in these diseases and is in line with reports of Treg down-regulation in Graves' disease 59 , and their upregulation in JIA SF. 11 For JIA, the same positive correlation was observed for the JIA-specific eGRN for enhancer activity in synovial fluid, but not for enhancer activity in PBMCs (Figure 5C The SLE-specific eGRN revealed a negative correlation of SLE enhancer activity and activation response in Th17 (Figure 5D). Many genes that have increased enhancer activity in SLE, and decreased expression in Th17, are related to IFN responses (i.e.…”

“…22 Cluster 9, which is upregulated in three of the four diseases, most strongly in JIA, is enriched in chemokine signalling pathways, and regulation of Treg differentiation, likely reflecting the important role of Tregs in JIA and other autoimmune diseases. 11,23 The psoriasis-specific cluster 10 is enriched in cell adhesion processes, which is in line with disease characteristics related to disturbances in cellular adhesion that can contribute to T cell dysregulation in psoriatic skin. 24 The Graves' disease-specific cluster 4, is enriched in more general processes related to inflammatory response, whereas the SLE-upregulated cluster 2 is significantly enriched in processes that are important in SLE pathogenesis like type 1 IFN signaling, and defence response to virus.…”

“…The strongest enrichments were observed for Th1, Th17, and Tregs in the psoriasis eGRN, and Tregs in the JIA eGRN, in line with the cell types important in these diseases. 11,20,57 Stimulationresponsive genes in Tregs were also significantly enriched in the Graves' disease and general AD eGRNs (although less strong than in JIA), likely reflecting the crucial role of Tregs in maintaining general immune tolerance and in line with their suggested dysregulation in ADs in general. 58 Next, we aimed to understand how enhancer remodelling in AD patients contributes to Th subset-specific activation.…”

“…25,26 We observed genes in the JIA network to be enriched in osteoclast differentiation, a process related to synovial joint inflammation characterising JIA patients, as well as regulation of Treg differentiation, a known cell type involved in JIA pathogenesis. 11,20 Lastly, we checked whether the AD eGRNs were enriched in genes from specific communities which were identified in the naive CD4+ T cell eGRN (Figure 3F). We found a significant enrichment of community 2 and 7 across all AD eGRNs, and community 17 across the general AD, Graves' disease, JIA and psoriasis eGRNs (Figure 4G/H).…”

T lymphocytes-related cell network in the pathogenesis of juvenile idiopathic arthritis: a key point for personalized treatment

“…Although clonally expanded SF T cells display markers of tissue residency, dominant SF T cell clones have been traced also in the circulation. Moreover, similar clones have been identified also in multiple affected joints [23 ▪ ]. Further studies are needed to understand if PD-1 or other markers are shared between cells of auto-reactive T cell clones, despite their location.…”