title: T Cells of Infants Are Mature, but Hyporeactive Due to Limited Ca2+ Influx.
abstract: CD4 T cells in human infants and adults differ in the initiation and strength of their responses. The molecular basis for these differences is not yet understood. To address this the principle key molecular events of TCR- and CD28-induced signaling in naive CD4 T cells, such as Ca2+ influx, NFAT expression, phosphorylation and translocation into the nucleus, ERK activation and IL-2 response, were analyzed over at least the first 3 years of life. We report dramatically reduced IL-2 and TNFα responses in naive CD31+ T cells during infancy. Looking at the obligatory Ca2+ influx required to induce T cell activation and proliferation, we demonstrate characteristic patterns of impairment for each stage of infancy that are partly due to the differential usage of Ca2+ stores. Consistent with those findings, translocation of NFATc2 is limited, but still dependent on Ca2+ influx as demonstrated by sensitivity to cyclosporin A (CsA) treatment. Thus weak Ca2+ influx functions as a catalyst for the implementation of restricted IL-2 response in T cells during infancy. Our studies also define limited mobilization of Ca2+ ions as a characteristic property of T cells during infancy. This work adds to our understanding of infants' poor T cell responsiveness against pathogens.
authors.affiliation: Department of Experimental Pediatrics, University Hospital, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Kristin
authors.initials: K
authors.lastname: Schmiedeberg
authors.affiliation: Clinic of Pediatric Surgery University Hospital, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Hardy
authors.initials: H
authors.lastname: Krause
authors.affiliation: Institute of Biometry and Medical Informatics University Hospital, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Friedrich-Wilhelm
authors.initials: FW
authors.lastname: Röhl
authors.affiliation: Institute for Molecular and Clinical Immunology, University Hospital, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Hartig
authors.affiliation: Department of Experimental Pediatrics, University Hospital, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Jorch
authors.affiliation: Department of Experimental Pediatrics, University Hospital, Otto-von-Guericke University, Magdeburg, Germany.
authors.forename: Monika C
authors.identifier: http://orcid.org/0000-0002-6838-3568
authors.initials: MC
authors.lastname: Brunner-Weinzierl
mesh_terms: D000293:Adolescent; D000328:Adult; D018106:CD28 Antigens / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D016572:Cyclosporine / Q000494:pharmacology; D004533:Egtazic Acid / Q000494:pharmacology; D005312:Fetal Blood / Q000166:cytology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008875:Middle Aged; D050778:NFATC Transcription Factors / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D055815:Young Adult
chemical_list: D018106:CD28 Antigens; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D014409:Tumor Necrosis Factor-alpha; D004533:Egtazic Acid; D016572:Cyclosporine; D002118:Calcium