Interferon-gamma (IFN delta) and interleukin-4 (IL4) production by human neonatal (NB) T cells is dramatically reduced compared to adult T cells. Decreased NB IFN-delta and IL4 production is pretranslationally-mediated, while IL2 production and mRNA accumulation is similar in the NB and adult. Since both IFN-delta and IL4 pleiotropically enhance the immune response, their decreased production may account, in part, for decreased antigen- specific and nonspecific immune function in early postnatal life, and for the neonate's predilection to severe infection. The goals of this proposal are to determine how IFN delta and IL4 production is developmentally regulated at a cellular and molecular level, and the in vivo effects of increased expression of these genes during early development. It is hypothesized that NB T cells will relatively lack a high IFN-delta of IL4-producing subset(s) definable by surface markers for putative memory cells when compared to adult T cells. NB and adult T cells will be fractionated on the basis of these and other markers and tested for IFN-delta/IL4 production using supernatant assays and mRNA using Northern blots and in situ hybridization. If results suggest that IFN delta/IL4 production is suppressed by a T cell subset, this suppressive activity will be characterized. It is hypothesized that decreased IFN delta or IL4 production and mRNA accumulation by NB T cells is not due to signal transduction differences between NB and adult cells, but is attributable to later transcriptional or post-transcriptional events. Transcription assays, genomic mapping, isolation of nuclear RNA, and pulse chase experiments will be used as necessary to test this hypothesis. If results point to a signal transduction difference, NB and adult T cells will be analyzed for differences in these events with available reagents. NB and adult T cell clones will be used to compliment these cellular and molecular studies by providing more homogeneous populations. Subsequently, the postnatal ontogeny of IFN-delta and/or IL4 production will be determined in human and mice. If young mice have a selective decrease in IFN delta and/or IL4 production, the hypothesis that this decreased production is beneficial to the ontogeny of normal immune function will be tested by injecting neonatal mice with these proteins or by expressing IFN delta/IL4 in transgenic animals. Mice will be closely analyzed for deleterious effects on the acquisition of T and B cell immunity in studies of immune function and immunohistopathology. This knowledge will allow a better assessment of the therapeutic potential of these proteins in treating the immunologically immature host.
