Session Title: T Cell Biology and Targets in Autoimmune Disease Poster II
Session Type: ACR Poster Session C
Session Time: 9:00AM-11:00AM
Background/Purpose: A key pathogenic event in rheumatoid arthritis (RA) is the formation of lasting lymphoid microstructures in the synovial tissue. It requires the transmigration of T cells from blood vessels into the tissue and the maneuvering of such T cells through the tissue matrix. T cells move in the tissue microenvironment by assembling cell membrane extensions, so-called podosomes. Regulation of podosome formation in T cells from RA patients is unexplored.
Methods: CD4 T cells were isolated from patients with seropositive RA and age-matched healthy controls. Tissue-residing T cells were examined in synovial biopsies. T cell motility was tested in 3D-collagen gels and in vivo by measuring T cell invasion into synovial tissue in a human synovium-SCID chimera model. Cellular metabolism of T cells was evaluated by quantifying stores of pyruvate, ATP, acetyl-CoA, and neutral fatty acids. We defined a module of 10 genes involved in regulation of the actin cytoskeleton and podosome formation, which was analyzed by RT-PCR, flow cytometry and immunohistochemistry.
Results: Compared to age-matched controls, RA T cells were high expressers of the Tyrosine Kinase Substrate with Five SH3 Domains (TKS5), an adaptor molecule critically involved in podosome formation, migrated more efficiently through 3D-gels and rapidly invaded into synovial tissues. TKS5 overexpression was sufficient to render T cells tissue-invasive; TKS5 knockdown abrogated the tissue-invasive behavior of RA T cells. TKS5 overexpression was associated with arthritogenic effector functions in the synovial tissue site, was regulated as part of a motility gene module and was found to be under metabolic control. Specifically, dampened glycolytic flux, resulting in low cellular pyruvate and ATP, induced TKS5 production and enhanced T cell hypermobility. T cells responded to energy deprivation with the accumulation of cytoplasmic lipid droplets, a prominent feature of tissue-resident synovial T cells. Restoring pyruvate stores or inhibiting fatty acid synthesis was sufficient to correct for the hypermobility of RA T cells in vitro and in vivo.
Conclusion: Synovial tissue invasion and arthritogenic T cell effector functions in RA patients are associated with dysregulated membrane function, specifically the formation of tissue-invasive podosomes. Defects in the T cell locomotion program are mechanistically linked to metabolic reprogramming, which diverts RA T cells from energy production to synthetic and proliferative functions. Understanding tissue invasiveness of RA T cells provides new opportunities to interfere with T cell trafficking and T cell invasion into specific tissue sites.
To cite this abstract in AMA style:Weyand CM, Shen Y, Li Y, Matteson EL, Goodman S, Goronzy J. Tissue-Invasive T Cells in Rheumatoid Arthritis [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). https://acrabstracts.org/abstract/tissue-invasive-t-cells-in-rheumatoid-arthritis/. Accessed May 30, 2020.
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