Deciphering the role of protein kinase A in the control of FoxP3 expression in regulatory T cells in health and autoimmunity

• Published in: Scientific reports Vol. 14; no. 1; pp. 17571 - 11
• Main Authors: Lepore, Maria Teresa, Bruzzaniti, Sara, La Rocca, Claudia, Fusco, Clorinda, Carbone, Fortunata, Mottola, Maria, Zuccarelli, Bruno, Lanzillo, Roberta, Brescia Morra, Vincenzo, Maniscalco, Giorgia Teresa, De Simone, Salvatore, Procaccini, Claudio, Porcellini, Antonio, De Rosa, Veronica, Galgani, Mario, Cassano, Silvana, Matarese, Giuseppe
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.07.2024; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250/38; 692/699/375; Autoimmunity; CD25 antigen; CD4 antigen; Cyclic AMP response element-binding protein; Cyclic AMP Response Element-Binding Protein - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; Female; Forkhead protein; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Foxp3 protein; Gene Expression Regulation; Humanities and Social Sciences; Humans; Immunoregulation; Kinases; Lymphocytes T; Male; Molecular modelling; multidisciplinary; Multiple sclerosis; Multiple Sclerosis - immunology; Multiple Sclerosis - metabolism; Phosphorylation; Protein kinase A; Proteins; Science; Science (multidisciplinary); T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-024-68098-z

The molecular mechanisms that govern differential T cell development from CD4 + CD25 - conventional T (Tconv) into CD4 + CD25 + forkhead-box-P3 + (FoxP3 + ) inducible regulatory T (iTreg) cells remain unclear. Herein, we investigated the relative contribution of protein kinase A (PKA) in this process. Mechanistically, we found that PKA controlled the efficiency of human iTreg cell generation through the expression of different FoxP3 splicing variants containing or not the exon 2. We found that transient PKA inhibition reduced the recruitment of cAMP-responsive element-binding protein (CREB) on regulatory regions of the FoxP3 gene, a condition that is associated with an impaired acquisition of their suppressive capacity in vitro. To corroborate our findings in a human model of autoimmunity, we measured CREB phosphorylation and FoxP3 levels in iTreg cells from treatment-naïve relapsing–remitting (RR)-multiple sclerosis (MS) subjects. Interestingly, both phospho-CREB and FoxP3 induction directly correlated and were significantly reduced in RR-MS patients, suggesting a previously unknown mechanism involved in the induction and function of human iTreg cells.