Vitamin A deficiency is estimated to compromise the health of nearly 250 million persons worldwide, contributing significantly to child mortality. In controlled studies in rats and mice, we have documented very low antibody responses to several bacterial antigens representative of both T-cell dependent and T-cell independent antigens. However, despite this immune dysfunction even severely deficient animals are capable of mounting a significant (even elevated) antigen-specific antibody response if they receive additional immune stimulation. Antibody production was augmented in vitamin A-deficient rats treated with either retinoic acid (RA) or polyriboinosinic acid:polyribocytidylic acid (PlC), a known inducer of interferons . The combination of RA?PIC resulted in a strikingly synergistic increase. Research from numerous laboratories has forwarded the concept that several lymphocyte surface proteins, besides the antigen receptors, provide important costimulation to T cells and B cells. We now postulate that CD38, a cell surface costimulatory molecule capable of activating signal transduction pathways and of forming a unique second messenger, cyclic ADP-ribose, is down-regulated in vitamin A deficiency. CD38 is induced by retinoids in several cell types. Our central hypothesis is that vitamin A deficiency impairs, while RA corrects or augments, the expression and functions of CD38. These concepts will be tested in 3 specific aims.
In Aim 1, we propose to determine whether RA regulates cell signaling triggered by ligation or co-ligation of CD38 and the T cell receptor (TCRJCD3) complexes. We will use the Jurkat T-cell model in which CD38 signaling has been studied previously, but vitamin A/RA was not a factor. Preliminary data support the induction of CD38 by RA in these cells.
In Aim 2, we will determine whether CD38 is required for the modulation of lymphocyte responses by RA and IFNs using wildtype and CD38-deficient mice.
In Aim 3, we will investigate the regulation of antibody production as a function of genotype (wildtype or CD38-/-), dietary vitamin A (deficient or adequate), and treatment (RA combined with PlC, or placebo). The results of these studies should clarify whether a lack of expression of CD38 is a cause of immune dysregulation in vitamin A deficiency. The combination of a cell culture approach, a genetic model, and nutritional-immunological studies should provide much needed information on the potential and the actual changes in T and B cell activation and differentiation related to vitamin A status, IFNs, their interaction, and CD38.
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