Session Information
Date: Monday, November 18, 2024
Title: T Cell Biology & Targets in Autoimmune & Inflammatory Disease Poster
Session Type: Poster Session C
Session Time: 10:30AM-12:30PM
Background/Purpose: Tertiary lymphoid structures (TLSs) are organized aggregates of immune cells that are frequently observed in the target tissues of chronic diseases. In patients with rheumatoid arthritis (RA), peripheral helper T (Tph) cells are markedly expanded in synovial tissues. Previous studies have indicated that both the presence of TLSs and the frequency of Tph cells are positively correlated with disease activity in RA, highlighting their contribution to the pathogenesis of autoimmunity. However, it remains largely elusive whether and how TLSs are involved in the maturation of Tph cells in local inflamed environment.
Methods: We performed scRNAseq combined with scTCRseq and CITEseq on CD4+ T cells from synovial tissue (ST, n=10), synovial fluid (SF, n=4) and peripheral blood (n=9). Additionally, scATACseq with CITEseq was performed on CD4 T cells from ST (n=1). We also conducted scRNAseq on fibroblast-like synoviocytes (FLSs) from ST (n=5). Formalin-fixed paraffin-embedded ST (n=1) was utilized for spatial transcriptomics data acquisition. For in vitro assays, Tph cells were sorted from SF, followed by CD3/CD28 stimulation for 3 days to evaluate proliferation or for 9 days to evaluate differentiation.
Results: Single-cell transcriptomic and epigenomic analyses identified two distinct subsets of Tph cells. Stem-like Tph (S-Tph) cells showed higher expressions of genes related to stemness. Conversely, effector-like Tph (E-Tph) cells were characterized by upregulation of genes involved in effector functions. Within synovial tissue, E-Tph cells demonstrated strong clonotype sharing with S-Tph cells, but not with T follicular helper cells, suggesting in situ maturation from S-Tph to E-Tph cells. In vitro, S-Tph cells showed self-renewal potential upon TCR stimulation while a proportion of cells downregulating stemness and upregulating effector signatures, supporting transition from S-Tph to E-Tph cells. To investigate cellular networks involving Tph cells, we obtained spatial transcriptomics data on synovial tissue and identified major cell types, including FLSs, endothelial cells, macrophages, T cells and B cells. S-Tph cells preferentially localized in TLSs with B cells, whereas E-Tph cells showed widespread distribution across the tissue interacting with macrophages. In search of the mechanism regulating S-Tph localization, we noted accumulation of chemokine transcripts surrounding blood vessels within TLSs. The proportion of a distinct chemokine-producing FLS cluster found in scRNAseq among FLSs positively correlated with that of S-Tph cells among CD4 T cells, suggesting the contribution of FLS-T cell axis to S-Tph localization in TLSs.
Conclusion: We identified two distinct Tph subsets by leveraging a multi-omics approach using samples from RA patients. S-Tph cells with self-renewal capacity localize in TLSs with B cells, whereas E-Tph cells are scattered at the periphery and outside of TLSs. This implies that E-Tph cells, which can be differentiated from S-Tph cells, migrate out of TLSs and then interact with macrophages. These data suggest that TLSs serve as unique niches for pathogenic CD4 T cell maturation in autoimmunity.
To cite this abstract in AMA style:
Masuo Y, Murakami A, Akamine R, Iri O, Murata K, Nishitani K, Ito H, Fujii T, Watanabe R, Iwasaki T, Nakamura S, Kuriyama S, Morita Y, Murakawa Y, Terao C, Okada Y, Hashimoto M, Matsuda S, Ueno H, Yoshitomi H. Distinct Proliferative and Special Properties of Peripheral Helper T Cells in RA Synovium [abstract]. Arthritis Rheumatol. 2024; 76 (suppl 9). https://acrabstracts.org/abstract/distinct-proliferative-and-special-properties-of-peripheral-helper-t-cells-in-ra-synovium/. Accessed .« Back to ACR Convergence 2024
ACR Meeting Abstracts - https://acrabstracts.org/abstract/distinct-proliferative-and-special-properties-of-peripheral-helper-t-cells-in-ra-synovium/