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

• Published in: ImmunoTargets and therapy 2024-11, Vol.13, p.595-616
• Main Authors: Becker, Antonia, Röhrich, Karoline, Leske, Amanda, Heinicke, Ulrike, Knape, Tilo, Kannt, Aimo, Trümper, Verena, Sohn, Kai, Wilken-Schmitz, Annett, Neb, Holger, Adam, Elisabeth, Laux, Volker, Parnham, Michael, Onasch, Valerie, Weigert, Andreas, Zacharowski, Kai, von Knethen, Andreas
• Format: Article
• Language: English
• Subjects: covid-19; crth2; foxp3; il-4; ngs; Original Research; pparγ; th2; treg
• ISSN: 2253-1556; 2253-1556
• DOI: 10.2147/ITT.S463601

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.BackgroundCOVID-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.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.MethodsTo 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.A significantly reduced count of total CD3+ T lymphocytes and the CD4+ and CD8+ subpopulations was observed. Also, the numbers of anti-inflammatory, resolutive Th2 cells and FoxP3-positive regulatory T cells (Treg) 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 Th2 marker is a receptor for prostaglandin D and its metabolic degradation product 15-deoxy-∆12,14-prostaglandin J2 (15d-PGJ2), an established endogenous PPARγ agonist. In line, we observed an increased PPARγ transactivation in response to 15d-PGJ2 treatment in HEK293T cells overexpressing CRTH2. Translating these data to primary T cells, we found that Th2 differentiation was associated with an increased expression of CRTH2. Interestingly, these CRTH2+ T cells were prone to apoptosis.ResultsA significantly reduced count of total CD3+ T lymphocyte