Innocent N. Mbawuike Ph.D.

The molecular, cellular and organismic basis for age-related CD8 + cytotoxic T cell (Tc) immunodeficiency and the impact of dysregulated Tc1/Tc2 cytokine expression in aged mice and elderly humans are being investigated using influenza virus as a model system. Our recent data suggest a Tc1 to Tc2 cytokine switch during the aging process resulting in reduced IFN-ã and increased IL-4 and IL-10 production, respectively, at both the protein and mRNA levels. IL-12 is the pivotal molecule for redirecting the immune response towards the Tc1 cytokine pathway. However, IL-12 remains unaltered in aging, except for a slight increase in the IL-12p40 moity relative to IL-12p35 subunit. However, we have recently demonstrated that the IL-12R 2 subunit, the signal transducing component of the IL-12R 1/â 2 dimer and which is selectively expressed on Tc1 T cells, is significantly down-regulated in CD8 + T cells from aged mice and elderly humans. The IL-12R12R 1 subunit is not changed. These results are consistent with our working hypothesis that CD8 + deficiency in aging is mediated by Tc1 cytokine deficiency. We have also observed an increased tendency of CD8 + T cells from aged mice to undergo apoptosis. The consequences of this apparent dysregulated cytokine expression and signal transduction, to age-related deficit in CD8 + CTL activity and apparent proneness to apoptosis are under intense investigation. Immuno-therapeutic approaches to reverse the CD8 + CTL deficiency are also being evaluated.

A long-standing interest in the laboratory includes development of novel influenza vaccines capable of stimulating MHC class I-restricted CD8+ CTL activity in elderly populations. The influenza nucleoprotein (NP) and matrix (M1) proteins are highly conserved among influenza A viruses and are major targets for induction of MHC class I-restricted CD8 + responses, and therefore are good candidates for enhancing the activity of influenza vaccines. To this end, NP and M1 genes have been cloned into baculovirus and expressed in insect cells or constructed as DNA vaccines incorporating various cytokine genes. These novel constructs are currently being investigated for induction of protective CD8 + CTL immunity at the mucosae. Promising vaccines will then be evaluated for restoration of CTL in old mice and elderly humans.

Recent Publications (PubMed)