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Defining the Differentiation Mechanisms of Pathogenic Granzyme K+ CD8 T cells 3937

Year: 2025
Type: article
Abstract: Description Granzyme K (GzmK)-expressing CD8 T cells are abundant in inflamed synovium in rheumatoid arthritis (RA) and are also found in cancer and other diseases. These CD8 T cells express GzmK, a protease that activates complement and stimulates fibroblasts to produce pro-inflammatory cytokines. Mechanisms driving expansion and differentiation of GzmK+ CD8 T cells remain unclear. GZMK+ CD8 T cells exhibit modest clonal expansion in RA synovium compared to blood, suggesting TCR-mediated expansion, but conditions favoring GzmK expression over GzmB are not known. We have found that bulk T cell stimulation using anti-CD3/CD28 antibody-coated beads (Dynabeads) induces GzmB, not GzmK expression. Importantly, this effect is mediated by cytokines, not TCR-crosslinking, because GzmB upregulation did not occur in the presence of tofacitinib, a Jak inhibitor which blocks signaling by many cytokine receptors. To study TCR-mediated signaling on CD8 T cells in a more natural context, we stimulated T cells with common viral peptides presented by HLA-A*02:01. We cultured healthy donor PBMCs with pooled peptides for 3 days with or without tofacitinib. While tetramer-positive (i.e. antigen-specific) cells were mostly GzmB+ following both peptide and Dynabead stimulation, we found that tofacitinib inhibited Dynabead-mediated GzmK/B changes but not peptide-mediated changes. Ongoing studies will test the effect of co-stimulation and cytokine signaling on CD8 T cell phenotypes. Funding Sources This work is supported by the NIH/NIAMS (K08AR081412) and the Rheumatology Research Foundation. Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)
DOI: 10.1093/jimmun/vkaf283.1679
Language: English
Subfield: Immunology
Open Access status: bronze
OpenAlex ID: W4416448806
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