T Cells of Infants Are Mature, but Hyporeactive Due to Limited Ca2+ Influx

• Published in: PloS one 2016-11, Vol.11 (11), p.e0166633-e0166633
• Main Authors: Schmiedeberg, Kristin, Krause, Hardy, Röhl, Friedrich-Wilhelm, Hartig, Roland, Jorch, Gerhard, Brunner-Weinzierl, Monika C
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Adults; Antigens; Biology and Life Sciences; Calcium - metabolism; Calcium influx; Calcium ions; CD28 antigen; CD28 Antigens - metabolism; CD4 antigen; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell activation; Cell Nucleus - metabolism; Cells, Cultured; Child; Child, Preschool; Cyclosporin A; Cyclosporine - pharmacology; Cytokines; Egtazic Acid - pharmacology; Fetal Blood - cytology; Gene expression; Humans; Immune system; Infant; Infant, Newborn; Infants; Infections; Interleukin 2; Interleukin-2 - metabolism; Kinases; Lymphocyte Activation - drug effects; Lymphocytes; Lymphocytes T; Medicine and Health Sciences; Middle Aged; NF-AT protein; NFATC Transcription Factors - metabolism; Pediatrics; People and Places; Phosphorylation; Platelet Endothelial Cell Adhesion Molecule-1 - metabolism; Research and Analysis Methods; Signal transduction; Signal Transduction - drug effects; Signaling; T cell receptors; T-cell receptor; Transcription factors; Translocation; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-α; Young Adult
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0166633

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.