Background/Purpose: Psoriasis is a systemic autoimmune/inflammatory condition that primarily affects the skin, but also other organ systems. Effector CD4⁺ T lymphocytes have been identified as a key contributor to inflammation and tissue damage, but underlying molecular mechanisms remain poorly understood.

The transcription factor CREMα plays a role in effector CD4+ T cell differentiation and activation in autoimmune/inflammatory conditions through altering cytokine gene expression, favoring effector T cells. The inhibitory surface co-receptor programmed death (PD-)1 plays a key role in controlling effector T cell generation and activation. This study investigated the involvement of CREMα in the regulation of PD-1 and effector T cell generation in psoriasis and psoriatic arthritis.

Methods: CD4+ T cells were isolated from peripheral blood of controls (N=13), psoriasis (N=13) and psoriatic arthritis patients (N=9) to examine effector cytokine expression (LUMINEX mRNA probe and MSD protein assays), and monitor CD4+ T cell subset distribution (flow cytometry) and co-inhibitory PD-1 mRNA and surface protein expression (flow cytometry, mRNA probes, qPCR). Using chromatin immunoprecipitation assays and luciferase reported assays, we investigated recruitment and trans-regulatory effects of CREMα on the PDCD1 promoter in wild-type and genetically modified CD4+ Jurkat T cells (CREMα overexpressing and CREMα-deficient cells).

Results: CD4+ T cells from psoriasis and psoriatic arthritis patients exhibit effector CD4+ T cell phenotypes with increased IL-17, and reduced IL-2 and inhibitory PD-1 co-receptor (mRNA and protein) expression. In effector CD4+ T cells, expression of the transcription factor CREMα is increased. Recruitment of CREMα to the PDCD1 proximal promoter results in its trans-repression and subsequently reduced PD-1 mRNA and protein expression. Expression of PD-1 associates with IL-2 expression and inversely correlates with IL-17A expression in wild-type and CREMα overexpressing Jurkat CD4+ T cells.

Conclusion: CREMα promotes effector CD4+ T cells in psoriasis and psoriatic arthritis through inhibition of PD-1 co-receptor expression. This contributes to imbalanced IL-2 and IL-17 expression in psoriasis and psoriatic arthritis and potentially may extend to other effector T cell mediated autoimmune/inflammatory conditions. This suggests CREMα:PD-1 axis is a promising target in the search for disease biomarkers and treatment targets.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/camp-response-element-modulator-crem%ce%b1-promotes-pd-1-effector-cd4-t-cells-in-psoriasis-and-psoriatic-arthritis/