Differential impact of high and low penetrance TNFRSF1A gene mutations on conventional and regulatory CD4+ T cell functions in TNFR1-associated periodic syndrome. Issue 5 (23rd November 2015)

• Record Type: Journal Article
• Authors: Pucino, Valentina; Lucherini, Orso Maria; Perna, Francesco; Obici, Laura; Merlini, Giampaolo; Cattalini, Marco; La Torre, Francesco; Maggio, Maria Cristina; Lepore, Maria Teresa; Magnotti, Flora; Galgani, Mario; Galeazzi, Mauro; Marone, Gianni; De Rosa, Veronica; Talarico, Rosaria; Cantarini, Luca; Matarese, Giuseppe
• Is Part Of: Journal of leukocyte biology. Volume 99:Issue 5(2016)
• Page Start: 761
• Page End: 769
• Publication Date: 2015-11-23
• Subjects: TRAPS -- Tregs -- Tconvs -- autoimmunity -- immune tolerance; Leucocytes -- Periodicals; Reticulo-endothelial system -- Periodicals; 571.96
• DOI: 10.1189/jlb.3A0915-399R
• Languages: English
• ISSNs: 0741-5400

Abstract

Abstract : Multiple variants of TNFRSF1A mutations may impact conventional and regulatory CD4 + T cell functions in TRAPS patients. Abstract: TNFR-associated periodic syndrome is an autoinflammatory disorder caused by autosomal-dominant mutations in TNFRSF1A, the gene encoding for TNFR superfamily 1A. The lack of knowledge in the field of TNFR-associated periodic syndrome biology is clear, particularly in the context of control of immune self-tolerance. We investigated how TNF-α/TNFR superfamily 1A signaling can affect T cell biology, focusing on conventional CD4 + CD25 − and regulatory CD4 + CD25 + T cell functions in patients with TNFR-associated periodic syndrome carrying either high or low penetrance TNFRSF1A mutations. Specifically, we observed that in high penetrance TNFR-associated periodic syndrome, at the molecular level, these alterations were secondary to a hyperactivation of the ERK1/2, STAT1/3/5, mammalian target of rapamycin, and NF-κB pathways in conventional T cells. In addition, these patients had a lower frequency of peripheral regulatory T cells, which also displayed a defective suppressive phenotype. These alterations were partially found in low penetrance TNFR-associated periodic syndrome, suggesting a specific link between the penetrance of the TNFRSF1A mutation and the observed T cell phenotype. Taken together, our data envision a novel role for adaptive immunity in the pathogenesis of TNFR-associated periodic syndrome involving both CD4 + conventional T cells and Tregs, suggesting a novel mechanism of inflammation in the context of autoinflammatory disorders.