Pneumococcal components induce regulatory T cells that attenuate the development of allergic airways disease by deviating and suppressing the immune response to allergen.
The induction of regulatory T cells (Tregs) to suppress aberrant inflammation and immunity has potential as a therapeutic strategy for asthma. Recently, we identified key immunoregulatory components of Streptococcus pneumoniae, type 3 polysaccharide and pneumolysoid (T+P), which suppress allergic airways disease (AAD) in mouse models of asthma. To elucidate the mechanisms of suppression, we have now performed a thorough examination of the role of Tregs. BALB/c mice were sensitized to OVA (day 0) i.p. and challenged intranasal (12-15 d later) to induce AAD. T+P was administered intratracheally at the time of sensitization in three doses (0, 12, and 24 h). T+P treatment induced an early (36 h-4 d) expansion of Tregs in the mediastinal lymph nodes, and later (12-16 d) increases in these cells in the lungs, compared with untreated allergic controls. Anti-CD25 treatment showed that Treg-priming events involving CD25, CCR7, IL-2, and TGF-β were required for the suppression of AAD. During AAD, T+P-induced Tregs in the lungs displayed a highly suppressive phenotype and had an increased functional capacity. T+P also blocked the induction of IL-6 to prevent the Th17 response, attenuated the expression of the costimulatory molecule CD86 on myeloid dendritic cells (DCs), and reduced the number of DCs carrying OVA in the lung and mediastinal lymph nodes. Therefore, bacterial components (T+P) drive the differentiation of highly suppressive Tregs, which suppress the Th2 response, prevent the Th17 response and disable the DC response resulting in the effective suppression of AAD.
Centre for Asthma and Respiratory Disease, University of Newcastle, Newcastle, New South Wales 2300, Australia;
Alison N
AN
Thorburn
Alexandra C
AC
Brown
Prema M
PM
Nair
Nina
N
Chevalier
Paul S
PS
Foster
Peter G
PG
Gibson
Philip M
PM
Hansbro
D000818:Animals; D001249:Asthma / Q000276:immunology*; D051940:B7-2 Antigen / Q000096:biosynthesis; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D007249:Inflammation / Q000276:immunology; D007376:Interleukin-2 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis; D008168:Lung / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D010047:Ovalbumin / Q000276:immunology; D011135:Polysaccharides, Bacterial / Q000008:administration & dosage / Q000276:immunology*; D054400:Receptors, CCR7 / Q000378:metabolism; D013296:Streptococcus pneumoniae / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D016212:Transforming Growth Factor beta / Q000378:metabolism
D051940:B7-2 Antigen; C515371:Ccr7 protein, mouse; D007376:Interleukin-2; D053645:Interleukin-2 Receptor alpha Subunit; D015850:Interleukin-6; D011135:Polysaccharides, Bacterial; D054400:Receptors, CCR7; D016212:Transforming Growth Factor beta; C026604:pneumococcal polysaccharide, type III; D010047:Ovalbumin