Identification of CRTH2 as a New PPARγ-Target Gene in T Cells Suggested CRTH2 Dependent Conversion of Th2 Cells as Therapeutic Concept in COVID-19 Infection

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Background: COVID-19 is a serious viral infection, which is often associated with a lethal outcome. Therefore, understanding mechanisms, which affect the immune response during SARS-CoV2 infection, are important. Methods: To address this, we determined the number of T cells in peripheral blood derived from intensive care COVID-19 patients. Based on our previous studies, evaluating PPARγ-dependent T cell apoptosis in sepsis patients, we monitored PPARγ expression. We performed a next generation sequencing approach to identify putative PPARγ-target genes in Jurkat T cells and used a PPARγ transactivation assay in HEK293T cells. Finally, we translated these data to primary T cells derived from healthy donors. Results: A significantly reduced count of total CD3 + T lymphocytes and the CD4 + and CD8 + subpopulations was observed. Also, the numbers of anti-inflammatory, resolutive T h 2 cells and FoxP3-positive regulatory T cells (T reg ) were decreased. We observed an augmented PPARγ expression in CD4 + T cells of intensive care COVID-19 patients. Adapted from a next generation sequencing approach in Jurkat T cells, we found the chemoattractant receptor‐homologous molecule expressed on T helper type 2 cells (CRTH2) as one gene regulated by PPARγ in T cells. This T h 2 marker is a receptor for prostaglandin D and its metabolic degradation product 15-deoxy-∆12,14-prostaglandin J 2 (15d-PGJ 2 ), an established endogenous PPARγ agonist. In line, we observed an increased PPARγ transactivation in response to 15d-PGJ 2 treatment in HEK293T cells overexpressing CRTH2. Translating these data to primary T cells, we found that T h 2 differentiation was associated with an increased expression of CRTH2. Interestingly, these CRTH2 + T cells were prone to apoptosis. Conclusion: These mechanistic data suggest an involvement of PPARγ in T h 2 differentiation and T cell depletion in COVID-19 patients. Keywords: T reg , PPARγ, T h 2, COVID-19, NGS, IL-4, CRTH2, FoxP3

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