REDUCED CYTOKINE PRODUCTION BY NEONATAL T CELLS

Stanford University, Stanford CA

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Abstract

DESCRIPTION (Adapted from Applicant's Description): The CD40-ligand (CD40-L) is a T cell-derived cytokine that, via its interaction with CD40, provides critical signals for B cell antibody production and isotype switching, and priming of T cells, particularly for production of interferon-gamma (IFN-gamma), a key mononuclear phagocyte (macrophage) activation factor. Since CD40-L protein and mRNA expression by human neonatal T cells is substantially reduced compared to adult T cells, this reduction may account, in part, for the susceptibility of the neonatal and young infant to infection with pathogens for which macrophage activation is protective, and for limitations in responses to protein vaccines at this age. This project will determine cellular and molecular mechanisms that limit production of CD40-L gene by neonatal T cells due to both its transcription and other cytokines during early post-natal life. The hypothesis will be tested that decreased expression of the CD40-L gene by neonatal T cells is due to both its reduced transcription and to decreased CD40-L mRNA stability. Transcriptional mechanisms will focus on the role of NFAT, a family of transcriptional activator proteins previously implicated in CD40-L gene expression, since preliminary results indicate that NFAT- directed transcription is reduced in neonatal T cells. These studies will use in vivo footprinting to evaluate the CD40-L promoter s NFAT binding sites, and anti-sense experiments to assess the role of individual NFAT proteins in CD40-L transcription in neonatal and adult T cells. A second aim will define the post-natal ontogeny of production of CD40-L and other T cell cytokines in response to recall vaccine antigens (hepatitis B and poliovirus) or surrogate polyclonal stimuli, e.g., TCR/CD3 engagement and B71 costimulation. Antigenically-naive adult T cells will serve as a comparison cell population. The human postnatal ontogeny of expression of CD38, a protein found on most thymocytes and neonatal T cells, but not adult T cells, and its relationship with CD40-L production will also be examined. This will test the hypothesis that decreased CD40-L production is accounted for by intrinsic, thymocyte-like immaturity of neonatal and infant CD38hi T cells. Finally, using a murine model, the hypothesis that TCR-independent bystander priming increases the capacity of T cells to produce CD40-L and other cytokines during early postnatal life will be tested. Together, these studies will substantially increase knowledge of the cellular and molecular mechanisms limiting T cell cytokine during early life, and may also show how cytokine production might be altered by pharmacologic or genetic approaches.