Human Neonatal Dendritic Cells Are Competent in MHC Class I Antigen Processing and Presentation

PLOS ONE, Sep 2007

Neonates are clearly more susceptible to severe disease following infection with a variety of pathogens than are adults. However, the causes for this are unclear and are often attributed to immunological immaturity. While several aspects of immunity differ between adults and neonates, the capacity of dendritic cells in neonates to process and present antigen to CD8+ T cells remains to be addressed. We used human CD8+ T cell clones to compare the ability of neonatal and adult monocyte-derived dendritic cells to present or process and present antigen using the MHC class I pathway. Specifically, we assessed the ability of dendritic cells to present antigenic peptide, present an HLA-E–restricted antigen, process and present an MHC class I-restricted antigen through the classical MHC class I pathway, and cross present cell-associated antigen via MHC class I. We found no defect in neonatal dendritic cells to perform any of these processing and presentation functions and conclude that the MHC class I antigen processing and presentation pathway is functional in neonatal dendritic cells and hence may not account for the diminished control of pathogens.

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Human Neonatal Dendritic Cells Are Competent in MHC Class I Antigen Processing and Presentation

et al (2007) Human Neonatal Dendritic Cells Are Competent in MHC Class I Antigen Processing and Presentation. PLoS ONE 2(9): e957. doi:10.1371/journal.pone.0000957 Human Neonatal Dendritic Cells Are Competent in MHC Class I Antigen Processing and Presentation Marielle C. Gold 0 1 Tammie L. Robinson 0 1 Matthew S. Cook 0 1 Laura K. Byrd 0 1 Heather D. Ehlinger 0 1 David M. Lewinsohn 0 1 Deborah A. Lewinsohn 0 1 0 Academic Editor: Esper Kallas, Federal University of Sao Paulo , Brazil 1 1 Department of Pulmonary and Critical Care Medicine, Oregon Health & Science University , Portland, Oregon , United States of America, 2 Portland VA Medical Center , Portland, Oregon , United States of America, 3 Department of Pediatrics, Oregon Health & Science University , Portland, Oregon , United States of America Neonates are clearly more susceptible to severe disease following infection with a variety of pathogens than are adults. However, the causes for this are unclear and are often attributed to immunological immaturity. While several aspects of immunity differ between adults and neonates, the capacity of dendritic cells in neonates to process and present antigen to CD8+ T cells remains to be addressed. We used human CD8+ T cell clones to compare the ability of neonatal and adult monocyte-derived dendritic cells to present or process and present antigen using the MHC class I pathway. Specifically, we assessed the ability of dendritic cells to present antigenic peptide, present an HLA-E-restricted antigen, process and present an MHC class I-restricted antigen through the classical MHC class I pathway, and cross present cell-associated antigen via MHC class I. We found no defect in neonatal dendritic cells to perform any of these processing and presentation functions and conclude that the MHC class I antigen processing and presentation pathway is functional in neonatal dendritic cells and hence may not account for the diminished control of pathogens. - INTRODUCTION About 2 million children die each year of infectious diseases (World Health Organization Maternal Health and Safe Motherhood Programme MSM96.7, 1996). Young infants are more susceptible to severe disease from infectious pathogens than are older children and adults [1]. Specifically, infections with respiratory syncytial virus, HIV, Streptococcus pneumoniae, Mycobacterium tuberculosis (Mtb) and Plasmodium sp. disproportionately cause morbidity and mortality in infants [2]. The causes for this are likely to be pleomorphic, and include the reduced frequency and diminished functional capacity of neonatal T cells [3]. While studies in both humans and mice demonstrate decreased T cell function in neonates, this defect can be overcome by the administration of strong adjuvants [4]. These data suggest that the defect might rest in the priming of nave T cells. Dendritic cells (DC) are unique in their capacity to present processed antigen to prime nave T cells in vivo: CD4+ T cells via the MHC II pathway, and CD8+ T cells via the MHC I pathway, respectively [5]. The results from studies evaluating the MHC II antigen processing and presentation pathway in neonates are equivocal but current reviews suggest neonatal DC may be defective in this regard [3,6]. However, little is known about the functionality of DC in antigen processing and presentation via the MHC I pathway in neonates. Ultimately, the most stringent functional test of DC function is their capacity to prime optimal T cell responses in vivo. While this is difficult to evaluate in humans, Salio et al. showed that DC from neonates could efficiently prime CD8+ T cells in vitro. However, priming was performed using DC loaded with antigenic peptide and again these DC were not tested for their ability to present processed antigen. To prime cytolytic CD8+ T cells, dendritic cells must first process cytosolic or exogenously-acquired antigens, load them onto newly synthesized MHC class I molecules, and transport the loaded MHC I molecules to the cell surface where they are available to stimulate CD8+ T cells. To date, no study has directly evaluated the capacity of human neonatal DC to process and present MHC class I antigens to CD8+-restricted T cells. Therefore, to address the hypothesis that the increased severity of disease associated with neonates is due to a defect in DC MHC I antigen processing and presentation, we performed a comprehensive study using monocyte-derived DC isolated from neonatal cord blood mononuclear cells (CBMC) and adult peripheral blood mononuclear cells (PBMC). We assessed the ability of DC to present antigenic peptide, present a MHC class Ib (HLA-E)restricted antigen, process and present a MHC class Ia antigen delivered through viral infection, and finally, cross present cellassociated antigen. This thorough functional examination of neonatal DC demonstrates that these cells are fully competent APC in their ability to process and present antigen to CD8+ T cells. RESULTS To directly as (...truncated)


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Marielle C. Gold, Tammie L. Robinson, Matthew S. Cook, Laura K. Byrd, Heather D. Ehlinger, David M. Lewinsohn, Deborah A. Lewinsohn. Human Neonatal Dendritic Cells Are Competent in MHC Class I Antigen Processing and Presentation, PLOS ONE, 2007, 9, DOI: 10.1371/journal.pone.0000957