Impaired BCR-induced NFAT1 nuclear translocation is implicated in low TACI expression in newborn B lymphocytes

Abstract

Abstract Neonates and infants have impaired immune responses to immunization compared to adults, resulting in high susceptibility to microbial infection. B cells have a central role in humoral immunity to immunization and infection, and signals via B cell receptor (BCR) are essential for the development and maintenance of B lymphocytes. T cell-independent type 2 (TI-II) antigens activate B lymphocytes through BCR and transmembrane activator and CAML interactor (TACI). Newborns, however, are unable to generate TI-II responses, partly because TACI expression is severely reduced in newborn B cells. Since BCR signaling regulates TACI expression, we hypothesized that suboptimal BCR activation may be responsible for the reduced TACI expression on newborn B cells. We found that engagement of murine newborn BCR with anti-mouse IgM f(ab′)2 results in ablated Nuclear Factor of Activated T-cells 1 (NFAT1) nuclear translocation as compared to adult BCR. Neither anti-IgM stimulation nor the calcium influx inducer, Ionomycin stimulation elicits a significantly different calcium influx profile between newborn and adult B cells, suggesting that the factors downstream of calcium influx are responsible for the suppression of NFAT1 activation. Diminished NFAT1 translocation is likely responsible for the reduced TACI expression in newborn B lymphocytes because blocking NFAT1 pathway with the selective NFAT inhibitor, FK506 prevents the upregulation of TACI in anti-IgM-stimulated adult B lymphocytes. We are currently investigating the activities of calcium-dependent NFAT1 activators calmodulin and calcineurin in newborn B lymphocytes to assess whether insufficiencies in these molecules are responsible for the ablated translocation of NFAT1.