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Infection and Immunity, February 2007, p. 810-819, Vol. 75, No. 2
0019-9567/07/$08.00+0     doi:10.1128/IAI.00228-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Chronic Exposure to Helicobacter pylori Impairs Dendritic Cell Function and Inhibits Th1 Development{triangledown}

Peter Mitchell,1,5 Conrad Germain,1 Pier Luigi Fiori,2 Wafa Khamri,5 Graham R. Foster,3 Subrata Ghosh,4 Robert I. Lechler,5 Kathleen B. Bamford,6,{dagger} and Giovanna Lombardi5*,{dagger}

Department of Immunology, Division of Medicine, Faculty of Medicine, Imperial College at Hammersmith Hospital, London, United Kingdom,1 Department of Biomedical Sciences, University of Sassari, Sassari, Italy,2 Hepatobiliary Group, Centre for Adult and Paediatric Gastroenterology, Bart's and The London, Queen Mary's School of Medicine and Dentistry, London, United Kingdom,3 Department of Gastroenterology, Division of Medicine, Faculty of Medicine, Imperial College at Hammersmith Hospital, London, United Kingdom,4 Department of Nephrology and Transplantation, Kings College London School of Medicine, Guy's Hospital Campus, London, United Kingdom,5 Department of Infectious Diseases and Immunity, Division of Investigative Sciences, Faculty of Medicine, Imperial College at Hammersmith Hospital, London, United Kingdom6

Received 10 February 2006/ Returned for modification 2 April 2006/ Accepted 13 October 2006

Helicobacter pylori causes chronic gastric infection that affects the majority of the world's population. Despite generating an inflammatory response, the immune system usually fails to clear the infection. Since dendritic cells (DCs) play a pivotal role in shaping the immune response, we investigated the effects of H. pylori on DC function. We have demonstrated that H. pylori increased the expression of activation markers on DCs while upregulating the inhibitory B7 family molecule, PD-L1. Functionally, H. pylori-treated DCs resulted in the production of interleukin-10 (IL-10) and IL-23 but not of alpha interferon (IFN-{alpha}). While very little or no IL-12 was produced to H. pylori alone, simultaneous ligation of CD40 on DCs induced IL-12 release. We also demonstrated that DCs treated with H. pylori-induced IFN-{gamma} production by allogeneic naive T cells. However, stimulation of DCs with H. pylori for an extended period of time impaired their ability to produce cytokines after CD40 ligation and limited their ability to promote IFN-{gamma} release, suggesting that the DCs had become exhausted by the prolonged stimulation. The effect of chronic infection with H. pylori on DC function was further investigated by focusing on DC development. Demonstrating that monocytes differentiated into DCs in the presence of H. pylori exhibited an exhausted phenotype with an impaired ability to produce IL-12 and a downregulation of CD1a. Our results raise the possibility that in chronic H. pylori infection DCs become exhausted after prolonged antigen exposure leading to suboptimal Th1 development. This effect may contribute to persistence of H. pylori infection.

* Corresponding author. Mailing address: Immunoregulation Laboratory, Department of Nephrology and Transplantation, 5th Fl., Thomas Guy House, King's College London School of Medicine at Guy's, King's College and St. Thomas' Hospitals, London SE1 9RT, United Kingdom. Phone: 44 (0) 2071887674. Fax: 44 (0) 2071887675. E-mail: giovanna.lombardi{at}kcl.ac.uk.

{triangledown} Published ahead of print on 13 November 2006.

Editor: J. L. Flynn

{dagger} K.B.B. and G.L. contributed equally to this study.

Infection and Immunity, February 2007, p. 810-819, Vol. 75, No. 2
0019-9567/07/$08.00+0     doi:10.1128/IAI.00228-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.





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