title: T regulatory cells control susceptibility to invasive pneumococcal pneumonia in mice.
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.
authors.affiliation: Department of Infection, Immunity and Inflammation, University of Leicester, United Kingdom.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Neill
authors.forename: Vitor E
authors.initials: VE
authors.lastname: Fernandes
authors.forename: Laura
authors.initials: L
authors.lastname: Wisby
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Haynes
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Ferreira
authors.forename: Ameera
authors.initials: A
authors.lastname: Laher
authors.forename: Natalie
authors.initials: N
authors.lastname: Strickland
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Gordon
authors.forename: Paul
authors.initials: P
authors.lastname: Denny
authors.forename: Aras
authors.initials: A
authors.lastname: Kadioglu
authors.forename: Peter W
authors.initials: PW
authors.lastname: Andrew
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000276:immunology; D004198:Disease Susceptibility / Q000276:immunology; D016503:Drug Delivery Systems; D005260:Female; D051858:Forkhead Transcription Factors / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D011018:Pneumonia, Pneumococcal / Q000188:drug therapy / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D013045:Species Specificity; D013296:Streptococcus pneumoniae / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014157:Transcription Factors / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors / Q000276:immunology*
chemical_list: D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C491746:Zfpn1a2 protein, mouse