Neonates are deficient in their ability to mount humoral immune responses. Although newborn lymphocytes are capable of eliciting specific antibodies in response to an antigenic challenge, the antibody responses are predominantly of the IgM class. In-vivo and in-vitro immune responses in newborn lymphocytes show a defect in isotype switching from IgM to IgG and IgA. The T cell surface molecule that delivers the contact-dependent signal for immunoglobulin isotype switching is the ligand for the B cell antigen CD4O (CD40 ligand, CD4OL). We have demonstrated that newborn lymphocytes express markedly decreased amounts of CD4OL and are severely deficient in their ability to undergo CD4OL-dependent immunoglobulin isotype switching to IgE. In the present proposal we wish to examine the molecular basis of the lack of CD40 ligand expression. We propose to Analyze CD4OL dependent isotype switching in infants. We will investigate the developmental regulation of CD4OL expression and assess the significance of reduced CD4OL expression by examining T cell directed IL-4 dependent IgE synthesis in infants versus adults. We will investigate whether delayed switching in transient hypogammaglobulinemia of infancy (THI) is associated with an abnormal delay in CD4OL expression. Analyze in detail transcriptional activation of the CD4OL gene. We propose to study the regulation of CD4OL expression in newborn T cells to understand the basis of their deficient expression of CD4OL. For that purpose, we will first determine the organization of the human CD4OL gene and characterize its upstream regulatory elements. c)Analyze the mechanism that lead to decreased CD4OL gene expression in cord blood T cells. We will examine whether low level expression of CD4OL in cord blood T cells is associated with altered methylation of the CD4OL gene upstream region. We will also analyze the cord blood T cells for the expression of trans-acting factors that regulate CD4OL expression. The results of our proposed studies should improve our understanding of the regulation of CD4OL expression in newborns and infants and may lead to the development of novel interventions that enhance isotype switching and of more effective vaccination regimens.
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