Giuseppe
Emeritus
[Source: PLoS Pathogens, full text: (LINK). Abstract, edited.]
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Research Article
Complement Mediated Signaling on Pulmonary CD103<SUP>+</SUP> Dendritic Cells Is Critical for Their Migratory Function in Response to Influenza Infection
Matheswaran Kandasamy, Poon C. Ying, Adrian W. S. Ho, Hermi R. Sumatoh, Andreas Schlitzer, Timothy R. Hughes, David M. Kemeny, B. Paul Morgan, Florent Ginhoux, Baalasubramanian Sivasankar
Affiliation: [See original page for the complete list.]
Abstract
Trafficking of lung dendritic cells (DCs) to the draining lymph node (dLN) is a crucial step for the initiation of T cell responses upon pathogen challenge. However, little is known about the factors that regulate lung DC migration to the dLN. In this study, using a model of influenza infection, we demonstrate that complement component C3 is critically required for efficient emigration of DCs from the lung to the dLN. C3 deficiency affect lung DC-mediated viral antigen transport to the dLN, resulting in severely compromised priming of virus-specific T cell responses. Consequently, C3-deficient mice lack effector T cell response in the lungs that affected viral clearance and survival. We further show that direct signaling by C3a and C5a through C3aR and C5aR respectively expressed on lung DCs is required for their efficient trafficking. However, among lung DCs, only CD103<SUP>+</SUP> DCs make a significant contribution to lung C5a levels and exclusively produce high levels of C3 and C5 during influenza infection. Collectively, our findings show that complement has a profound impact on immune regulation by controlling tissue DC trafficking and highlights a potential utility for complement as an adjuvant in novel vaccine strategies.
Author Summary
Influenza is a global health problem frequented by epidemics and pandemics. Current vaccines against influenza offer limited protection hence the need for reformulation and repeated vaccination. There is a pressing need to develop newer vaccines that are able to generate T cell response. In order to develop such vaccines, there is a need to understand how T cell responses are generated during influenza infection. Influenza specific T cell responses are generated by the dendritic cells (DCs) in the lung. Upon influenza infection, DCs in the lung carry viral peptides to the draining lymph node (dLN) to initiate an immune response. Thus, migration of DCs from the lung to the dLN is an important step in the initiation of influenza specific T cell response. We now show that activation products of the complement system interact with their receptors on the DCs, which signals for the DCs to migrate from the lung to the dLN. Thus, our results reveal a previously unknown function for complement in mediating lung DC migration during influenza infection and highlight its potential as an adjuvant in novel vaccine strategies.
Citation: Kandasamy M, Ying PC, Ho AWS, Sumatoh HR, Schlitzer A, et al. (2013) Complement Mediated Signaling on Pulmonary CD103<SUP>+</SUP> Dendritic Cells Is Critical for Their Migratory Function in Response to Influenza Infection. PLoS Pathog 9(1): e1003115. doi:10.1371/journal.ppat.1003115
Editor: Andrew Pekosz, Johns Hopkins University - Bloomberg School of Public Health, United States of America
Received: June 13, 2012; Accepted: November 20, 2012; Published: January 10, 2013
Copyright: ? 2013 Kandasamy et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was funded by the Agency for Science, Technology and Research (A*STAR; http://www.a-star.edu.sg/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: shiv@sics.a-star.edu.sg
-Complement Mediated Signaling on Pulmonary CD103<SUP>+</SUP> Dendritic Cells Is Critical for Their Migratory Function in Response to Influenza Infection
Matheswaran Kandasamy, Poon C. Ying, Adrian W. S. Ho, Hermi R. Sumatoh, Andreas Schlitzer, Timothy R. Hughes, David M. Kemeny, B. Paul Morgan, Florent Ginhoux, Baalasubramanian Sivasankar
Affiliation: [See original page for the complete list.]
Abstract
Trafficking of lung dendritic cells (DCs) to the draining lymph node (dLN) is a crucial step for the initiation of T cell responses upon pathogen challenge. However, little is known about the factors that regulate lung DC migration to the dLN. In this study, using a model of influenza infection, we demonstrate that complement component C3 is critically required for efficient emigration of DCs from the lung to the dLN. C3 deficiency affect lung DC-mediated viral antigen transport to the dLN, resulting in severely compromised priming of virus-specific T cell responses. Consequently, C3-deficient mice lack effector T cell response in the lungs that affected viral clearance and survival. We further show that direct signaling by C3a and C5a through C3aR and C5aR respectively expressed on lung DCs is required for their efficient trafficking. However, among lung DCs, only CD103<SUP>+</SUP> DCs make a significant contribution to lung C5a levels and exclusively produce high levels of C3 and C5 during influenza infection. Collectively, our findings show that complement has a profound impact on immune regulation by controlling tissue DC trafficking and highlights a potential utility for complement as an adjuvant in novel vaccine strategies.
Author Summary
Influenza is a global health problem frequented by epidemics and pandemics. Current vaccines against influenza offer limited protection hence the need for reformulation and repeated vaccination. There is a pressing need to develop newer vaccines that are able to generate T cell response. In order to develop such vaccines, there is a need to understand how T cell responses are generated during influenza infection. Influenza specific T cell responses are generated by the dendritic cells (DCs) in the lung. Upon influenza infection, DCs in the lung carry viral peptides to the draining lymph node (dLN) to initiate an immune response. Thus, migration of DCs from the lung to the dLN is an important step in the initiation of influenza specific T cell response. We now show that activation products of the complement system interact with their receptors on the DCs, which signals for the DCs to migrate from the lung to the dLN. Thus, our results reveal a previously unknown function for complement in mediating lung DC migration during influenza infection and highlight its potential as an adjuvant in novel vaccine strategies.
Citation: Kandasamy M, Ying PC, Ho AWS, Sumatoh HR, Schlitzer A, et al. (2013) Complement Mediated Signaling on Pulmonary CD103<SUP>+</SUP> Dendritic Cells Is Critical for Their Migratory Function in Response to Influenza Infection. PLoS Pathog 9(1): e1003115. doi:10.1371/journal.ppat.1003115
Editor: Andrew Pekosz, Johns Hopkins University - Bloomberg School of Public Health, United States of America
Received: June 13, 2012; Accepted: November 20, 2012; Published: January 10, 2013
Copyright: ? 2013 Kandasamy et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was funded by the Agency for Science, Technology and Research (A*STAR; http://www.a-star.edu.sg/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: shiv@sics.a-star.edu.sg
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