Background/Purpose: Innate-like T cells comprise on average 10-15% of peripheral T cell and have T-cell receptors (TCRs) that engage ligands other than classic HLA class I or class II molecules displaying peptide. These cell types are characterized by a poised state at baseline, enabling rapid cytokine production upon stimulation. Innate-like T cells include natural killer T (NKT) cells, mucosal associated invariant T (MAIT) cells, and γδT cells, which in turn are divided into subsets based on their TCRδ gene expression (Vδ1, Vδ2, Vδ3, etc). The exact ligands for most γδTCR subsets are not clear, and there are indications that γδT cells can be activated independently of the TCR via NKG2D, which binds stress-induced ligands such as MICA and MICB, which are expressed in inflammatory synovium.

Methods: Synovial fluid mononuclear cells were collected from patients with clinical diagnoses of seropositive rheumatoid arthritis (RA), seronegative RA, spondyloarthritis (SpA), and juvenile idiopathic arthritis (JIA). Peripheral blood mononuclear cells were collected from patients with seropositive RA, seronegative RA, SpA, and JIA and from healthy controls (HC). We assessed the frequency and phenotypes of Vδ1, Vδ2, and other γδT cells using flow cytometry. We also stimulated synovial fluid mononuclear cells with CD3/CD28 beads or with phorbol myristate acetate (PMA) and ionomycin and measured cytokine production by Vδ1 and Vδ2 cells by intracellular cytokine staining. Statistics were performed by Kruskal-Wallis test.

Results: Vδ1 cells are enriched in synovial fluid from patients with JIA (7.61±4.07% vs 0.78±0.57% in HC blood, p<0.05), whereas non-Vδ1/Vδ2 γδT cells are elevated in synovial fluid from seropositive RA (7.20±4.05% vs 0.48±0.15% in seropositive RA blood, p<0.01). While a high frequency of all γδT cell subsets expressed NKG2D, other surface markers differed between γδT cell subsets and between blood and synovial fluid γδT cells. For example, CD69 was expressed at a high frequency on all three γδT cell subsets from synovial fluid from all four types of autoimmune arthritis but not from blood. CD25 is expressed at a higher rate among non-Vδ1/Vδ2 γδT cells from seropositive RA synovial fluid than from any of the other synovial fluid groups or from blood (36.7±16.4% vs 8.8±2.2% in seropositive RA blood, p<0.01). PD-1 was expressed by about half of Vδ1 and non-Vδ1/Vδ2 γδT cells from blood and was upregulated mainly on non-Vδ1/Vδ2 γδT cells in synovial fluid. Vδ2 cells, in contrast, expressed PD-1 at a low frequency in both blood and synovial fluid. Upon stimulation with PMA and ionomycin, both Vδ1 and Vδ2 cells from synovial fluid of all four types of autoimmune arthritis produced IFNγ and TNF at robust frequencies. However, only Vδ1 cells produced IL17A, with a frequency similar to CD4 T cells.

Conclusion: These findings suggest that Vδ1, Vδ2, and non-Vδ1/Vδ2 γδT cells represent cell populations with distinct functions in the blood and synovial fluid from patients with autoimmune arthritis. Additional studies are needed to further elucidate their roles in RA pathogenesis.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/v%ce%b41-v%ce%b42-and-other-%ce%b3%ce%b4t-cells-in-blood-and-synovium-of-rheumatoid-arthritis-and-other-autoimmune-arthritides/