ATP affects follicular T helper cells during pediatric RSV infection

RUSSO, CONSTANZA; RAIDEN, SILVINA; ALGIERI, SILVIA; BRUERA, MARÍA JOSÉ; DE CARLI, NORBERTO; SARLI, MARIAM; CAIROLI, HÉCTOR; DE LILLO, LEONARDO; MORALES, LAURA DANIELA; SEERY, VANESA; OTERO, ADRIÁN; SANANEZ, INÉS; SIMAZ, NANCY; ALFIERO, G; MOYA, N; AEDO PORTELA, L; SALCEDO PEREIRA, M; FERRERO, FERNANDO; GEFFNER, JORGE; ARRUVITO, LOURDES

San Luis

Congreso; Reunión Anual SAI 2023; 2023

SAI

Background:Respiratory syncytial virus (RSV) infection represents a major burdenin infants. Follicular T helper cells (Tfh) play a critical role inthe generation of protective antibodies. The purinergic receptorP2X7R has been recognized as a signature gene of Tfh cells. Theexpression and function of P2X7R on Tfh cells from RSV-infectedinfants have not been analyzed previously.Aims:1) To characterize circulating Tfh cells (cTfh) in RSV-children 2) Toquantify IL-21 levels in serum, ATP and P2X7R cleaved soluble form(P2X7Rs) levels in serum and nasopharyngeal aspirates (NPA) 3) Toanalyze the membrane P2X7R expression in cTfh 4) To explore thebiologic response of cTfh to ATP (P2X7R agonist) and KN-62 (P2X7Rantagonist) 5) To study the correlation with the Clinical DiseaseSeverity Score (CDSS).Methods:Plasma,NPA and PBMCs from children with non-severe (n=46) and severe RSVinfection (n=26) and controls (n=23) were used. Results:Weobserved decreased cTfh frequency in non-severe (n=30) and severeRSV-infected infants (n=15) compared with controls (n=23,p<0.0001).Severe RSV-children presented the lowest IL-21 serum levels comparedto non-severe (p<0.01) and controls (p<0.0001). Plasma IL-21levels positively correlated with cTfh frequency (r=0.31,p<0.01).Severe RSV-children also exhibited higher levels of ATP in plasma andNPA in comparison with non-severe (p<0.05) and controls (p<0.01).Plasma ATP levels negatively correlated with cTfh frequency(r=-0.3,p<0.05). Interestingly, severe children showed anincreased frequency of P2X7R+cTfh cells related to non-severe(p<0.05) and controls (p<0.01). ATP serum levels positivelycorrelated with the membrane receptor expression (r=0.44,p<0.05).Importantly, ATP exposure decreased cTfh proliferative response anddenovoIL-21 production, while also inducing apoptosis (p<0.001,n=14).These effects were significantly restored with KN-62. Moreover, thelevels of P2X7Rs, due to negative receptor regulation, were higher innon-severe than in severe RSV-infected children (p<0.001).Finally, plasma and NPA ATP levels positively correlated with CDSS(r=0.6,p<0.0001), while IL-21 plasma levels correlated negatively(r=-0.36,p<0.005).Conclusions:RSVinfection induces up-regulation of P2X7 receptor in cTfh cellsmodifying their function. Levels of ATP in plasma and NPA could beuseful biomarkers of disease severity. A better understanding of theTfh cells in young infants is critical for vaccine development.p { line-height: 115%; text-align: left; orphans: 2; widows: 2; margin-bottom: 0.25cm; direction: ltr; background: transparent }