Respiratory syncytial virus reduces STAT3 phosphorylation in human memory CD8 T cells stimulated with IL-21

Krist Helen Antunes,André Becker,Lidiane Leitão,Isadora Lape,Mauricio M Rigo,Caroline Franceschina,Mariana D’Ávila Da Cunha,Deise Do Nascimento De Freitas,Ana Paula Duarte De Souza,Leonardo Araújo Pinto,Renato T Stein

doi:10.1038/s41598-019-54240-9

Abstract

Respiratory syncytial virus (RSV) is a common cause of childhood lower respiratory tract infections. The recent failure of a vaccine candidate based on recombinant F protein underlines the urgent need to better understand the protective human memory immune response against RSV. Signal transducer and activator of transcription 3 (STAT3) protein is a transcription factor that promotes the maturation of the memory CD8 T cell response in cooperation with IL-10 and IL-21. However, the role of STAT3 in the memory CD8 T cell response during RSV infection remains to be elucidated. We found that in infants with bronchiolitis infected with RSV, the expression of STAT3 detected in nasal washes is reduced when compared to that in infants infected by other viruses. In vitro, RSV impairs STAT3 phosphorylation induced by IL-21 in purified human memory CD8 T cells. In addition, RSV decreases granzyme B production by memory CD8 T cells, reducing its cytotoxic activity against RSV-infected epithelial pulmonary cell lines. Together, these data indicate that RSV modulates the IL-21/STAT3 pathway in human memory CD8 T cells, and this could be a mechanism to be further explored to improve the memory response against the infection.

Highlights

Respiratory syncytial virus (RSV) is the leading pathogen of lower respiratory diseases in children less than 5 years old and is associated with bronchiolitis and pneumonia diagnoses
Given the importance of signal transducer and activator of transcription 3 (STAT3) signaling on human memory CD8 T cells, we further measured STAT3 phosphorylation on serine 727 in cells isolated from the blood of healthy adult subjects
Since IL-21 plays an important role in memory CD8 T cell responses by activating STAT3, purified human memory CD8 T cells were incubated with RSV for 1 h and subsequently stimulated with IL-21 for 30 min to measure pSTAT3

Summary

Introduction

Respiratory syncytial virus (RSV) is the leading pathogen of lower respiratory diseases in children less than 5 years old and is associated with bronchiolitis and pneumonia diagnoses. Neutralizing antibodies and cellular immune responses are involved in protection against the virus, but these mechanisms are not yet fully understood[5]. Peripheral blood RSV-specific cell-mediated cytotoxic immune responses are more frequent in infants with bronchiolitis with mild infection than in those with severe infection[8]. In experimental RSV infection of adults, CD8 T cells are associated with a reduction in pulmonary viral load[9]. Patients with STAT3 mutations present with more viral infections[15,16] and show impairment in memory CD8 T cell responses[17]. The roles of IL-21 and STAT3 in the memory CD8 T cell response during RSV infection are unknown, and addressing this issue is the main goal of the present study

Methods

Results

Conclusion