New Tech Provides Insights Into the Pathogenesis of Psoriatic Arthritis

Also, unique environmental clues are critical for chemotaxis of immune cells to the synovial tissue. For example, CXCR3 expression by CD8 T cells and the local production of CXCR3 ligands (CXCL9, CXCL10) likely explain the considerable accumulation of CD8 T cells in the synovial tissue and fluid of PsA patients. Interestingly, tissue-resident CD8 T cell clusters express the skin/gut markers (ITGA1: CD49a), supporting their potential migration from the skin or gut to the synovium or, alternatively, moving from the synovium to the skin or gut (see Figure 1).²⁹

The application of CyTOF and single-cell RNA sequence analysis identified three CD8 T cell subsets in PsA synovial fluid characterized by class II expression (human leukocyte antigen-DR [HLA-DR] low vs. high) and ZNF683—a gene classically expressed by tissue-resident memory T (TRM) cells.

The detection of proliferative markers like MK167 and STMN1 and the evidence of clonal expansion based on T cell receptor (TCR) α and ß sequencing in CD8 T cells provide evidence of local activation and suggest antigen-driven CD8 T cell activation and expansion inPsA synovial fluid. Also, expression of genes involved in the production of cytotoxic molecules (i.e., granzyme A, B, H and K) and chemokines (i.e., ccl4, ccl5) by HLA-DR high CD8 TRM cells was also identified.²⁹

Thus, the findings generated from examination of synovial fluid reveal a predominant CD8 T cell response with clonal features and polyfunctional cells that release various cytokines critical for activation of stromal cells along with adaptive and innate immune cells in target tissue. Also, the capacity of CD8 T cells to produce chemokines facilitates recruitment of additional immune cells resulting in the amplification and persistence of local inflammation.

Studies in our lab, currently focused on understanding the functional heterogeneity of CD8 T cells and their migratory and functional characteristics in PsA patients with a humanized murine model, may lead to strategies that modulate their pathogenic functions and alleviate skin and musculoskeletal inflammation.

The studies outlined above demonstrated a dominant CD8 cell response in the synovial fluid but these cells expressed few activation markers. In contrast, monocytes in PsA synovial fluid showed a prominent activation profile. CyTOF analysis showed that monocytes and macrophages in synovial fluid produced significant amounts of CCL2, which is likely responsible for recruiting inflammatory monocytes to the inflamed synovia and osteopontin, a matricellular protein with multiple functions including upregulation of IL-1ß and modulation of signaling and chemoattractant pathways in monocytes, fibroblasts and bone.^30-32