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AJRCMB Articles in Press. Published on 30-November-2015 as 10.1165/rcmb.2015-0297OC
Airway CD8⁺ T-cells are associated with lung injury during infant viral respiratory tract infection Thomas J. Connors1,2, Thyyar M. Ravindranath1, Kara L. Bickham2, Claire L. Gordon2, Feifan Zhang3, Bruce Levin3, John S. Baird1, and Donna L. Farber2,4,5 1 Department of Pediatrics, Columbia University Medical Center, New York, NY, 10032 2 Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032 3 Department of Biostatistics, Columbia University Mailman School of Public Health, New York, NY 10032 4 Department of Surgery, Columbia University Medical Center, New York, NY 10032 5 Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032 Correspondence and requests for reprints should be addressed to Donna L Farber, Ph.D. Columbia Center for Translational Immunology, 630 West 168th St, Mailbox 127 New York NY, 10032. E-mail [email protected]. Phone (212) 305-6030; Fax (212) 3420550 Author Contributions: T.J.C, T.M.R, K.L.B, J.S.B, and D.L.F designed research. T.J.C, C.L.G., K.L.B performed research. T.J.C, T.M.R, B.L, F.Z, J.S.B, and D.L.F analyzed data. T.J.C, T.M.R, B.L, J.S.B, and D.L.F wrote the manuscript. Supported by National Institutes of Health Grants R01AI100119-01 (D.L.F) and S10RR027050 (CCTI Flow Cytometry Core), and Irving Institute CTO pilot award UL1 TR0040 (K.L.B.) Running Head; Cytotoxic Lymphocytes and Viral Lung Injury 1.20 Immunology/Inflammation: Human Studies Manuscript Word Count: 3762 At a Glance Commentary: Scientific Knowledge on the Subject: The increased susceptibility of infants to morbidity and mortality from viral respiratory tract infections has been attributed to the immature nascent immune response, although the precise mechanisms remain undefined. Research in mice indicates that local T-cell responses at the tissue site of infection are essential for controlling infections; however, the nature of respiratory immunity in early life and its impact on protective immunity and immunopathology remains undefined. What This Study Adds to the Field: This study demonstrates that the immune response in the airway is associated with disease severity while the systemic response is uninformative. Specifically, we detected an increased ratio of CD8+ to CD4+ T-cells in the airways of virally infected children with acute lung injury compared to those infected without lung injury. This finding raises the possibility of adaptive immune response dysregulation contributing to severe consequences of infection in children. This article has an online data supplement, which is accessible from this issue’s table of content online at www.atsjournal.org
Copyright © 2015 by the American Thoracic Society
AJRCMB Articles in Press. Published on 30-November-2015 as 10.1165/rcmb.2015-0297OC
Page 2 of 40
ABSTRACT Rationale: Infants and young children are disproportionately susceptible to severe complications from respiratory viruses, although the underlying mechanisms remain unknown. Recent studies show that the T-cell response in the lung is important for protective responses to respiratory infections, although details on the infant/pediatric respiratory immune response remain sparse. Objectives: To characterize the local versus systemic immune response in infants and young children with respiratory failure from viral respiratory tract infections and its association to disease severity. Methods: Daily airway secretions were sampled from infants and children ≤ 4 years of age receiving mechanical ventilation due to respiratory failure from viral infection or non-infectious causes. Samples were examined for immune cell composition and activation then compared to similar parameters in blood and to clinical disease severity. Measurements and Main Results: Innate immune cells and total CD3+ T-cells were present in similar proportions in airway aspirates derived from infected and uninfected groups; however, the CD8:CD4 T-cell ratio was markedly increased in the airways of patients with viral infection compared to uninfected patients, and specifically in infected infants with acute lung injury. T-cells in the airways were phenotypically and functionally distinct from those in blood with activated/memory phenotypes and increased cytotoxic capacity. Conclusions: We identified a significant increase in airway cytotoxic CD8+ T-cells in infants with lung injury from viral respiratory tract infection that was distinct from the T-cell profile in circulation and associated with increasing disease severity. Airway sampling could therefore be diagnostically informative for assessing immune responses and lung damage. Word Count: 248 Key Words: infant immunity, viral pneumonia, lung injury, immunopathology
1 Copyright © 2015 by the American Thoracic Society
Page 3 of 40
AJRCMB Articles in Press. Published on 30-November-2015 as 10.1165/rcmb.2015-0297OC
INTRODUCTION Viral respiratory tract infections (VRTI) are the most prevalent cause of disease worldwide, with infants and young children
AJRCMB Articles in Press. Published on 30-November-2015 as 10.1165/rcmb.2015-0297OC
Airway CD8⁺ T-cells are associated with lung injury during infant viral respiratory tract infection Thomas J. Connors1,2, Thyyar M. Ravindranath1, Kara L. Bickham2, Claire L. Gordon2, Feifan Zhang3, Bruce Levin3, John S. Baird1, and Donna L. Farber2,4,5 1 Department of Pediatrics, Columbia University Medical Center, New York, NY, 10032 2 Columbia Center for Translational Immunology, Columbia University Medical Center, New York, NY 10032 3 Department of Biostatistics, Columbia University Mailman School of Public Health, New York, NY 10032 4 Department of Surgery, Columbia University Medical Center, New York, NY 10032 5 Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY 10032 Correspondence and requests for reprints should be addressed to Donna L Farber, Ph.D. Columbia Center for Translational Immunology, 630 West 168th St, Mailbox 127 New York NY, 10032. E-mail [email protected]. Phone (212) 305-6030; Fax (212) 3420550 Author Contributions: T.J.C, T.M.R, K.L.B, J.S.B, and D.L.F designed research. T.J.C, C.L.G., K.L.B performed research. T.J.C, T.M.R, B.L, F.Z, J.S.B, and D.L.F analyzed data. T.J.C, T.M.R, B.L, J.S.B, and D.L.F wrote the manuscript. Supported by National Institutes of Health Grants R01AI100119-01 (D.L.F) and S10RR027050 (CCTI Flow Cytometry Core), and Irving Institute CTO pilot award UL1 TR0040 (K.L.B.) Running Head; Cytotoxic Lymphocytes and Viral Lung Injury 1.20 Immunology/Inflammation: Human Studies Manuscript Word Count: 3762 At a Glance Commentary: Scientific Knowledge on the Subject: The increased susceptibility of infants to morbidity and mortality from viral respiratory tract infections has been attributed to the immature nascent immune response, although the precise mechanisms remain undefined. Research in mice indicates that local T-cell responses at the tissue site of infection are essential for controlling infections; however, the nature of respiratory immunity in early life and its impact on protective immunity and immunopathology remains undefined. What This Study Adds to the Field: This study demonstrates that the immune response in the airway is associated with disease severity while the systemic response is uninformative. Specifically, we detected an increased ratio of CD8+ to CD4+ T-cells in the airways of virally infected children with acute lung injury compared to those infected without lung injury. This finding raises the possibility of adaptive immune response dysregulation contributing to severe consequences of infection in children. This article has an online data supplement, which is accessible from this issue’s table of content online at www.atsjournal.org
Copyright © 2015 by the American Thoracic Society
AJRCMB Articles in Press. Published on 30-November-2015 as 10.1165/rcmb.2015-0297OC
Page 2 of 40
ABSTRACT Rationale: Infants and young children are disproportionately susceptible to severe complications from respiratory viruses, although the underlying mechanisms remain unknown. Recent studies show that the T-cell response in the lung is important for protective responses to respiratory infections, although details on the infant/pediatric respiratory immune response remain sparse. Objectives: To characterize the local versus systemic immune response in infants and young children with respiratory failure from viral respiratory tract infections and its association to disease severity. Methods: Daily airway secretions were sampled from infants and children ≤ 4 years of age receiving mechanical ventilation due to respiratory failure from viral infection or non-infectious causes. Samples were examined for immune cell composition and activation then compared to similar parameters in blood and to clinical disease severity. Measurements and Main Results: Innate immune cells and total CD3+ T-cells were present in similar proportions in airway aspirates derived from infected and uninfected groups; however, the CD8:CD4 T-cell ratio was markedly increased in the airways of patients with viral infection compared to uninfected patients, and specifically in infected infants with acute lung injury. T-cells in the airways were phenotypically and functionally distinct from those in blood with activated/memory phenotypes and increased cytotoxic capacity. Conclusions: We identified a significant increase in airway cytotoxic CD8+ T-cells in infants with lung injury from viral respiratory tract infection that was distinct from the T-cell profile in circulation and associated with increasing disease severity. Airway sampling could therefore be diagnostically informative for assessing immune responses and lung damage. Word Count: 248 Key Words: infant immunity, viral pneumonia, lung injury, immunopathology
1 Copyright © 2015 by the American Thoracic Society
Page 3 of 40
AJRCMB Articles in Press. Published on 30-November-2015 as 10.1165/rcmb.2015-0297OC
INTRODUCTION Viral respiratory tract infections (VRTI) are the most prevalent cause of disease worldwide, with infants and young children
