T Regulatory Cells Control Susceptibility to Invasive Pneumococcal Pneumonia in Mice

Daniel R Neill,Laura Wisby,Peter W Andrew,Vitor E Fernandes,Daniela M Ferreira,Paul Denny,Aras Kadioglu,Stephen B Gordon,Natalie Strickland,Ameera Laher,Andrew R Haynes

doi:10.1371/journal.ppat.1002660

Abstract

Streptococcus pneumoniae is an important human pathogen responsible for a spectrum of diseases including pneumonia. Immunological and pro-inflammatory processes induced in the lung during pneumococcal infection are well documented, but little is known about the role played by immunoregulatory cells and cytokines in the control of such responses. We demonstrate considerable differences in the immunomodulatory cytokine transforming growth factor (TGF)-β between the pneumococcal pneumonia resistant BALB/c and susceptible CBA/Ca mouse strains. Immunohistochemistry and flow cytometry reveal higher levels of TGF-β protein in BALB/c lungs during pneumococcal pneumonia that correlates with a rapid rise in lung Foxp3+Helios+ T regulatory cells. These cells have protective functions during pneumococcal pneumonia, because blocking their induction with an inhibitor of TGF-β impairs BALB/c resistance to infection and aids bacterial dissemination from lungs. Conversely, adoptive transfer of T regulatory cells to CBA/Ca mice, prior to infection, prolongs survival and decreases bacterial dissemination from lungs to blood. Importantly, strong T regulatory cell responses also correlate with disease-resistance in outbred MF1 mice, confirming the importance of immunoregulatory cells in controlling protective responses to the pneumococcus. This study provides exciting new evidence for the importance of immunomodulation during pulmonary pneumococcal infection and suggests that TGF-β signalling is a potential target for immunotherapy or drug design.

Highlights

Streptococcus pneumoniae is an important human pathogen that accounts for significant morbidity and mortality, in high-risk groups such as children, the elderly and the immunocompromised
Streptococcus pneumoniae is a major human bacterial pathogen that causes a wide range of diseases including pneumonia, meningitis, sepsis and ear infections
We identify an important role in natural resistance against pneumococcal pneumonia for a group of cells – known as T regulatory cells – that control the immune response to pneumococcal infection

Summary

Introduction

Streptococcus pneumoniae (the pneumococcus) is an important human pathogen that accounts for significant morbidity and mortality, in high-risk groups such as children, the elderly and the immunocompromised. It has been demonstrated that CD4+ T cells contribute to protective immunity to invasive pneumococcal pneumonia, as MHC-II-deficient mice, which have severely reduced numbers of CD4+ T cells, are highly susceptible to infection [5]. Whilst there is an expanding body of work outlining the roles of inflammatory T cell subsets [6,7,8,9], little has been made of regulatory and anti-inflammatory T cells and their influence on the outcome of pneumococcal pneumonia. This is an important gap in our understanding of the immunology of pneumococcal disease

Results

Discussion

Conclusion