Session Type: ACR Poster Session A
Session Time: 9:00AM-11:00AM
In the pre-clinical rheumatoid arthritis (RA) prodrome, autoantibodies and transient symptoms may develop. Pre-clinical autoantibody development suggests concomitant expansion of autoantigen-specific CD4+ follicular helper T cells (TFH). A biased T cell receptor (TCR) repertoire in the joints of recent-onset RA patients suggests clonal expansion in early RA. Antigen-specific CD4+ T cells were clonally expanded at onset of murine collagen-induced arthritis. To model the pathogenetic role played by autoantigen-specific CD4+ T cells before and after autoantibody development, we longitudinally assessed the frequency, phenotype and clonotypic composition of the dominant aggrecan89-103 epitope-specific CD4+ T cell repertoire in proteoglycan-induced arthritis (PGIA). We aimed to elucidate how and when autoantigen-specific CD4+ T cells contribute to arthritis progression.
PGIA was induced in BALB/cAnNCrl and BALB/c FoxP3-GFP mice by intraperitoneal injection (prime and two booster injections) of recombinant G1 epitope of human proteoglycan (rhG1-PG) emulsified in DDA adjuvant. MHC class II (IAd)-aggrecan89-103 tetramers and single-cell multiplex-nested PCR-TCR sequencing was used to study splenic aggrecan89-103-specific CD4+ T cells before and after onset of PGIA. Quantitative and phenotypic analysis of aggrecan89-103-specific CD4+ T cells was assessed by flow cytometry, based on the expression of CD44, CD62L, FoxP3, CXCR5 and PD1 and index sorting in TCR sequencing experiments. ELISA measured anti-human PG-specific antibodies.
Splenic aggrecan89-103-specific CD4+ T cells expanded in the prodrome before the detection of autoantibodies or persistent disease activity. Aggrecan89-103-specific CD4+ T cells shifted from naïve to activated effector memory (TEM) and TFH, associated with a loss of aggrecan89-103-specific FoxP3+ Treg. CD4+ TCR β-chain variable genes (TRBV)13-1+, 13-2+ and 2+ aggrecan89-103-specific TEM and TFH cells clonally expanded in the prodromal period during transient joint inflammation. After clonotype depletion with anti-TRBV13 mAb, disease onset was delayed, autoantibody titres reduced and arthritis attenuated. Three public TRBV13+ clonotypes were shared between mice and between different BALB/c strains. All public clonotypes had conserved amino acid residues arising from convergent recombination, supporting selection of TCR for antigen recognition.
Antigen-specific public clonotypes expand during the prodromal period, prior to development of autoantibodies. Therefore longitudinal antigen-specific TCR repertoire analysis prior to high titre autoantibody development may identify expanding autoreactive CD4+ T cell clones in individuals at risk of RA.
To cite this abstract in AMA style:Wehr P, Nel H, Law SC, Jansen D, La Gruta N, Reid H, Rossjohn J, Thomas R. Pre-Clinical Clonally-Expanded aggrecan89-103–Specific CD4+ T Cells Are a Target for Autoimmune Arthritis Prevention [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/pre-clinical-clonally-expanded-aggrecan89-103-specific-cd4-t-cells-are-a-target-for-autoimmune-arthritis-prevention/. Accessed December 15, 2019.
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pre-clinical-clonally-expanded-aggrecan89-103-specific-cd4-t-cells-are-a-target-for-autoimmune-arthritis-prevention/