Increased IL-12 induced STAT-4 signaling in CD8 T cells from aged mice
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Series/Report no.:2008 Edward F. Hayes Graduate Research Forum. 22nd
Aging is associated with poor immune function leading to increased susceptibility to infectious diseases and the development of immune associated disorders. Specific deficiencies in CD4 T cell function have been identified whereby CD4 T cells from old mice have defective T cell receptor mediated antigen-specific responses compared to young T cells. Several of the defects described in T cells in old age can be attributed to dysfunctional cell signaling through the T cell receptor. Immune cell function is also dependent on cytokine production, and the capacity of cells to respond to cytokines. We have previously shown that a subset of CD8 T cells from the lungs of aged mice produce IFN-γ when exposed to IL-12 in an antigen-independent manner. Furthermore, IL-12 responsive CD8 T cells are present in apparently healthy old mice and represent a population that can mediate early non-specific control of Mycobacterium tuberculosis. For this reason understanding the mechanism underlying their ability to respond to IL-12 in the absence of a TCR signal may identify an alternate pathway to optimize protective immune responses in the elderly. We investigated the ability of CD8 T cells from old mice to respond to IL-12 by determining the expression of the IL-12 receptor on the surface of young and old CD8 T cells, as well as by quantifying the activation of the downstream signaling molecule, STAT-4. We found IL-12Rβ2 expression on pulmonary CD8 T cells to be equivalent between young and old mice, and therefore hypothesized that IL-12 signaling in pulmonary CD8 T cells was increased in old age. To test this hypothesis, single cell suspensions from young and old mice were given IL-12 for 4 hours, and STAT-4 phosphorylation in CD8 T cells was determined using flow cytometric analysis. In response to IL-12, pulmonary CD8 T cells from old mice had increased levels of phosphorylated STAT-4 within individual CD8 T cells, and old mice possessed significantly more CD8 T cells that could phosphorylate STAT-4 in response to IL-12 compared to young, leading to an increased number of CD8 T cells that could secrete IFN-γ. To confirm STAT-4 activation was a direct consequence of IL-12 stimulation, STAT-4 phosphorylation was determined in purified CD8+ cells from young and old mice. IL-12-induced STAT-4 phosphorylation was detected in purified CD8+ cells from both ages of mice, illustrating that IL-12 could act directly on CD8+¬ cells. Importantly, the proportion of CD8+ cells that could phosphorylate STAT-4, and the amount of phosphorylated STAT-4 in each cell was significantly greater in CD8+ cells from old mice. These data demonstrate that old mice possess a substantial population of CD8 T cells exhibiting increased STAT-4 phosphorylation in response to IL-12, which ultimately leads to enhanced IFN-γ production. We therefore define a mechanism for the increase in IL-12-induced IFN-γ secretion by CD8 T cells in old mice. A more comprehensive understanding of the unique contribution of CD8 T cells to innate immunity in old mice could lead to the development of more efficacious therapies in the elderly for combating pulmonary infections.
Biological Sciences: 1st Place (The Ohio State University Edward F. Hayes Graduate Research Forum)
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