CCR4⁺CD8⁺ T cells clonally expand to differentiated effectors in murine psoriasis and in human psoriatic arthritis

Abstract

Psoriasis is a chronic inflammatory skin disease with an autoimmune component and associated with joint inflammation in up to 30% of cases. To investigate autoreactive T cells, we developed an imiquimod‐induced psoriasis‐like inflammation model in K5‐mOVA.tg C57BL/6 mice expressing ovalbumin (OVA) on the keratinocyte membrane, adoptively transferred with OT‐I OVA‐specific CD8+ T cells. We evaluated the expansion of OT‐I CD8+ T cells and their localization in skin, blood, and spleen. scRNA‐seq and TCR sequencing data from patients with psoriatic arthritis were also analyzed. In the imiquimod‐treated K5‐mOVA.tg mouse model, OT‐I T cells were markedly expanded in the skin and blood at early time points. OT‐I T cells in the skin showed mainly CXCR3+ effector memory phenotype, whereas in peripheral blood there was an expansion of CCR4+CXCR3+ OT‐I cells. At a later time point, expanded OVA‐specific T‐cell population was found in the spleen. In patients with psoriatic arthritis, scRNA‐seq and TCR sequencing data showed clonal expansion of CCR4+ TCM cells in the circulation and further expansion in the synovial fluid. Importantly, there was a clonotype overlap between CCR4+ TCM in the peripheral blood and CD8+ T‐cell effectors in the synovial fluid. This mechanism could play a role in the generation and spreading of autoreactive T cells to the synovioentheseal tissues in psoriasis patients at risk of developing psoriatic arthritis.

From the Skin to Distant Sites: T Cells in Psoriatic Disease

“…In this mouse model, it was shown that prolonged skin inflammation induced by imiquimod favors the activation of OT-I CD8 + T cells specific to the cutaneous self-antigen [65]. These cells had a CCR4 + phenotype and were found in peripheral blood and in an expanded pool of memory T cells in the spleen.…”

“…Sorted CCR7 + CD45RA − CXCR3 − cells from peripheral blood mononuclear cells (PBMCs) stimulated with αCD3/αCD28 beads were analyzed at different time points. On day 3, after T cell receptor (TCR) stimulation, all CCR4 − -enriched T CM cells shifted their phenotype to double positive CCR4 + CXCR3 + T CM , and at later time points a small fraction of cells that were single positive for CXCR3 and a fraction of cells with the T EM phenotype were detected [65].…”

“…To understand if an analogous mechanism could play a role in spreading tissue damage and inflammation to the joints in human PsA, we analyzed scRNA-seq data paired with TCR αβ chain sequencing in paired samples of PsA patients' peripheral blood and synovial fluid CD8 T cells [96]. Clonotype analysis showed a clonal expansions in the CCR4 + T CM subset in the peripheral blood of PsA patients as compared to their CCR4 negative counterpart; moreover, there was a clonal link between these expanded CCR4 + clones in the blood and clones found in the expanded CXCR3 + effectors in the synovial fluid of PsA patients [65]. This finding reinforces the importance of antigen-specific cells (likely self-antigen-specific T cells) entering the systemic circulation in generating inflammation and damage to the joints of PsA patients, with a possible shift in their phenotype towards more differentiated and cytotoxic effectors (Figure 2).…”