HELPER T LYMPHOCYTE FUNCTION IN VITAMIN A DEFICIENCY

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Vitamin A is essential for many biological functions. The close relationship between vitamin A and immunity is particularly significant for human health. Mildly A-deficient children die of infections at up to 12 times the rate of well-nourished children. Supplementary vitamin A reduces the incidence of cancer and infectious disease. Vitamin A-deficiency has a striking effect on antibody responses; IgG responses decrease by 80% compared to controls at a stage in A-deficiency when IgM responses are unaffected. This immune response defect is attributable to helper T lymphocytes. The A- deficient T cells sense foreign antigen, but do not signal 8 cells to grow and produce IgG. This block is fully reversed in vitro by retinyl acetate. The molecular basis for the helper T cell functional block in vitamin A-deficient animals is completely unknown. We formulated two hypotheses to explain this defect. Our results are consistent with a type-2 helper T cell failure to transduce activation signals, or with retinoid control over interleukin gene expression. Experiments are proposed to define the molecular basis for the vitamin A-dependence of T cells. Signal transduction through T cell antigen receptor molecules and through accessory molecules in A-deficient (A-) and A-sufficient (A+) T cells will be analyzed. B cell stimulatory lymphokine production by A+ and A- T cells will be quantitated with and without added vitamin A. If signal transduction is normal, but lymphokine production is decreased, lymphokine mRNA steady state levels will be determined, and if different, transcript initiation rates studied. In addition, evidence for a nuclear retinoid receptor will be sought. Finally, retinoids will be tested in vitro and in vivo for their ability to sustain the immune response. This research will describe the molecular basis for the retinoid dependence of helper T lymphocyte function. It will also contribute to a model for the vitamin's role in cell growth and differentiation, generally. Finally, it will provide insight into the relationship between retinoids, infectious disease, and possibly cancer.