Journal Article

Ontogeny of Toll-Like Receptor Mediated Cytokine Responses of Human Blood Mononuclear Cells

Wilson, Christopher B., Fortuno, Edgardo S., Corbett, Nathan P., Sutherland, Darren P., Kallos, Arlene, Hajjar, Adeline M., Crabtree, Juliet, Hawkins, Natalie R., Ho, Kevin C., Self, Steven G., Blimkie, Darren, Kollmann, Tobias R., Rein-Weston, Annie, Lavoie, Pascal M., Turvey, Stuart E., Cai, Bing

2010

Overview

Newborns and young infants suffer increased infectious morbidity and mortality as compared to older children and adults. Morbidity and mortality due to infection are highest during the first weeks of life, decreasing over several years. Furthermore, most vaccines are not administered around birth, but over the first few years of life. A more complete understanding of the ontogeny of the immune system over the first years of life is thus urgently needed. Here, we applied the most comprehensive analysis focused on the innate immune response following TLR stimulation over the first 2 years of life in the largest such longitudinal cohort studied to-date (35 subjects). We found that innate TLR responses (i) known to support Th17 adaptive immune responses (IL-23, IL-6) peaked around birth and declined over the following 2 years only to increase again by adulthood; (ii) potentially supporting antiviral defense (IFN-α) reached adult level function by 1 year of age; (iii) known to support Th1 type immunity (IL-12p70, IFN-γ) slowly rose from a low at birth but remained far below adult responses even at 2 years of age; (iv) inducing IL-10 production steadily declined from a high around birth to adult levels by 1 or 2 years of age, and; (v) leading to production of TNF-α or IL-1β varied by stimuli. Our data contradict the notion of a linear progression from an 'immature' neonatal to a 'mature' adult pattern, but instead indicate the existence of qualitative and quantitative age-specific changes in innate immune reactivity in response to TLR stimulation.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adaptive immunity / Adult / Adults / Age / Age Factors / Antigen-Presenting Cells - drug effects / Antigen-Presenting Cells - immunology / Antigen-Presenting Cells - metabolism / Antigens / B cells / Bacillus / Biology / Birth / Child, Preschool / Childbirth & labor / Children / Cohort Studies / Comparative analysis / Cytokines / Cytokines - immunology / Cytokines - metabolism / Dendritic Cells - drug effects / Dendritic Cells - immunology / Dendritic Cells - metabolism / Fetuses / Flow cytometry / Health aspects / Helper cells / Herpes viruses / Human behavior / Humans / Immune response / Immune system / Immunity / Immunology / Infant / Infant, Newborn / Infants / Infections / Innate immunity / Interferon / Interleukin 10 / Interleukin 12 / Interleukin 23 / Interleukin 6 / Leukocytes (mononuclear) / Leukocytes, Mononuclear - drug effects / Leukocytes, Mononuclear - immunology / Leukocytes, Mononuclear - metabolism / Lipopeptides - pharmacology / Lipopolysaccharides - pharmacology / Lymphocytes T / Medical research / Medicine / Middle Aged / Morbidity / Mortality / Neonates / Newborn babies / Newborn infants / Oligodeoxyribonucleotides - pharmacology / Ontogeny / Pediatrics / Proteins / Stimulation / T cell receptors / Toll-Like Receptor 2 - agonists / Toll-Like Receptor 2 - immunology / Toll-Like Receptor 4 - agonists / Toll-Like Receptor 4 - immunology / Toll-Like Receptor 7 - agonists / Toll-Like Receptor 7 - immunology / Toll-Like Receptor 8 - agonists / Toll-Like Receptor 8 - immunology / Toll-Like Receptor 9 - agonists / Toll-Like Receptor 9 - immunology / Toll-like receptors / Toll-Like Receptors - agonists / Toll-Like Receptors - immunology / Tumor necrosis factor-α / Vaccines / Young Adult / γ-Interferon