Tissue‐Resident Memory CD8+ T Cells From Skin Differentiate Psoriatic Arthritis From Psoriasis

Abstract

Objective To compare immune cell phenotype and function in psoriatic arthritis (PsA) versus psoriasis in order to better understand the pathogenesis of PsA. Methods In‐depth immunophenotyping of different T cell and dendritic cell subsets was performed in patients with PsA, psoriasis, or axial spondyloarthritis and healthy controls. Subsequently, we analyzed cells from peripheral blood, synovial fluid (SF), and skin biopsy specimens using flow cytometry, along with high‐throughput transcriptome analyses and functional assays on the specific cell populations that appeared to differentiate PsA from psoriasis. Results Compared to healthy controls, the peripheral blood of patients with PsA was characterized by an increase in regulatory CD4+ T cells and interleukin‐17A (IL‐17A) and IL‐22 coproducing CD8+ T cells. One population specifically differentiated PsA from psoriasis: i.e., CD8+CCR10+ T cells were enriched in PsA. CD8+CCR10+ T cells expressed high levels of DNAX accessory molecule 1 and were effector memory cells that coexpressed skin‐homing receptors CCR4 and cutaneous lymphocyte antigen. CD8+CCR10+ T cells were detected under inflammatory and homeostatic conditions in skin, but were not enriched in SF. Gene profiling further revealed that CD8+CCR10+ T cells expressed GATA3, FOXP3, and core transcriptional signature of tissue‐resident memory T cells, including CD103. Specific genes, including RORC, IFNAR1, and ERAP1, were up‐regulated in PsA compared to psoriasis. CD8+CCR10+ T cells were endowed with a Tc2/22‐like cytokine profile, lacked cytotoxic potential, and displayed overall regulatory function. Conclusion Tissue‐resident memory CD8+ T cells derived from the skin are enhanced in the circulation of patients with PsA compared to patients with psoriasis alone. This may indicate that aberrances in cutaneous tissue homeostasis contribute to arthritis development.

Combined Single Cell Transcriptome and Surface Epitope Profiling Identifies Potential Biomarkers of Psoriatic Arthritis and Facilitates Diagnosis via Machine Learning

“…While, to our knowledge, the role of dnTs and HSPCs in PSA has not been extensively investigated, dnT cells have been reported to infiltrate psoriatic skin as well as participate in IL-23/IL-17 signaling in mouse models of psoriasis ( 34 ) and spondyloarthritis ( 35 ), and the proliferation and differentiation of HSPCs is currently known to respond to systemic interferon and TNF signaling ( 36 ). While we observed increased peripheral Tregs in PSA patients, whether this subset is generally increased or decreased in PSA is still unclear in light of conflicting results found in other studies ( 37 , 38 ).…”

Translational Research Studies Unraveling the Origins of Psoriatic Arthritis: Moving Beyond Skin and Joints

“…Of interest is the comparison between skin of PsO and PsA patients, which is informative to understand the relation between the two diseases. These kinds of studies are unfortunately scarce (53,54), but crosssectional comparisons do point to molecular differences between skin of PsO and PsA patients (54).…”

“…CD8+ T cells are polyfunctional enabling the production of a wide range of cytokines both in skin and joints (66). In blood of PsA patients, more memory CD8+ T cells have been found compared to healthy controls and PsO patients (53), underlining a possible important role of memory CD8+ T cells in PsA. Also in synovial fluid of PsA patients, these CD8+ cells are abundantly present and are clonally expanded more extensively than CD4+ T cells (66,71).…”

“…There have already been efforts made to investigate molecular differences between skin of PsO and PsA patients in crosssectional studies. Differences have been reported (53,54), but it is unclear if these observed molecular changes in skin precede or follow PsA development which stresses the importance to study patients during the transition from PsO to PsA using a prospective study design with serial tissue sampling. Although this is highly challenging, only this will show which molecular and cellular processes in the skin change during the transition from PsO to PsA.…”

Early Origins of Psoriatic Arthritis: Clinical, Genetic and Molecular Biomarkers of Progression From Psoriasis to Psoriatic Arthritis

“…An early study of skin from PsA patients (n = 15) vs. Pso patients (n = 5) and normal control skin (n = 4) identified increased numbers of CD45Ro T-cells, greater vascularity, the presence of B-cells, and increased numbers of DR +epidermal cells as markers for arthritis in patients with Pso (34). While these findings have not been replicated, a more recent study by Leijten et al identified CCR10+ CD8+ T cells as being enriched in PsA peripheral blood (35). CCR10+ CD8+ T cells were detected under inflammatory and homeostatic conditions in Pso skin but were not enriched in synovial fluid.…”