SPECIFIC INVOLVEMENT OF CONVENTIONAL AND REGULATORY CD4+ T CELLS IN TUMOR NECROSIS FACTOR RECEPTOR-ASSOCIATED PERIODIC SYNDROME (TRAPS)

Abstract Tumor necrosis factor-receptor associated periodic syndrome (TRAPS) is a dominantly inherited auto-inflammatory disorder caused by mutations in TNFRSF1A, the gene encoding for tumour necrosis factor receptor superfamily 1A. The mechanism of inflammation in TRAPS is still unknown. In particular the involvement of adaptive immunity in autoinflammatory disorders hasn't been investigated yet. In this project we investigated how TNFa/TNRSF1A signalling network regulates T cell responses. In particular, we focused on conventional CD4+CD25- (Tconv) and regulatory CD4+CD25+ (Treg) T cell functions in TRAPS patients carrying either high or low penetrance mutation in TNFRSF1A gene (HP-TRAPS and LP-TRAPS, respectively). HP-TRAPS showed an upregulation of several inflammation-related molecular signalling pathways in Tconv cells. In addition, these patients had a lower frequency of peripheral Treg cells which also displayed a defective suppressive phenotype. These alterations were partially found in LP-TRAPS who also carried a milder symptomatology thus suggesting suggest a specific link between the penetrance of the TNFRSF1A mutation and the T cell phenotype. Taken together, these data envision a novel role for adaptive immunity in the pathogenesis of TRAPS involving both CD4+ Tconv and Treg cells raising a novel mechanism of inflammation in the context of auto-inflammatory disorders.