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.

Frontline Science: PECAM-1 (CD31) expression in naïve and memory, but not acutely activated, CD8+ T cells

“…15 Nevertheless, CD31 has come to be widely used as a marker of recent thymic emigrants within the CD4 + CD45RA + T cell population. [15][16][17][18][19][20][21][22] Importantly, temporal regulation of PECAM-1 expression in T cells other than those that are CD4 + CD45RA + has been much less well studied. Early studies reported that, following its down-regulation in response to TCR stimulation, CD31 remains absent from mature CD4 + T cells throughout subsequent maturation events, including establishment of memory (i.e., CD4 + CD45RA − CD45RO + ).…”

Understanding Adaptive Immune System as Reinforcement Learning

“…The early fluctuation is due to the small β in the learning process (see Materials and Methods). This early fluctuation promotes exploration of the system, which might be related to the downregulation of the Th function in the early infancy periods [46] It should be noted that, in a real biological situation, the learning also starts with the Th clone distribution pre-trained in the thymus. Such pre-training may be optimized to facilitate and expedite subsequent learning, possibly by evading the very early exploring stage of the learning [47].…”

Cooperation between T cell receptor and Toll-like receptor 5 signaling for CD4 + T cell activation

“…To challenge our merged TCR+TLR5 model, we studied the response of naïve CD4 + T cells to stimulation of the TCR alone, of TLR5 alone, of the TCR together with TLR5, and of the TCR together with CD28, in strong and weak activation conditions, and assessed the phosphorylation of p65, c-Jun, and CREB1. As strong stimulus, we used a high concentration (1 µg/ml) of each anti-CD3 and anti-CD28 antibody crosslinked with a goat anti-mouse antibody, as reported by others (71)(72)(73)(74)(75). We further used a lower concentration (0.1 µg/ml) of each antibody to achieve a weak or suboptimal stimulation (74)(75)(76)(77).…”

“…As strong stimulus, we used a high concentration (1 µg/ml) of each anti-CD3 and anti-CD28 antibody crosslinked with a goat anti-mouse antibody, as reported by others (71)(72)(73)(74)(75). We further used a lower concentration (0.1 µg/ml) of each antibody to achieve a weak or suboptimal stimulation (74)(75)(76)(77). Although all the evaluated molecules showed a basal level of phosphorylation, statistically significantly greater phosphorylation was achieved when the cells were exposed to strong stimuli of TCR alone (for CREB activation), or of TCR and costimulatory signals (for p65 and c-Jun) (Fig.…”