title: Interleukin-12 is sufficient to promote antigen-independent interferon-gamma production by CD8 T cells in old mice.
abstract: Numerous functional defects have been identified in naive T cells from aged mice, including deficiencies in proliferation, cytokine production and signal transduction. It is well documented that the ratio of naïve to memory T cells significantly decreases with age resulting in the majority of T cells from aged hosts expressing activated/memory T-cell markers (CD44(hi)), yet it is unclear whether T cells with a CD44(hi) phenotype in aged hosts are functionally equivalent to T cells with a similar phenotype in young hosts. We have identified a population of CD44(hi) CD8 T cells in old mice that are capable of secreting interferon-gamma (IFN-gamma) in response to interleukin-12 (IL-12) stimulation. This occurred in the absence of T-cell receptor engagement, a function that was not observed in CD8 T cells from young mice. This phenotype was associated with increased IL-12 receptor beta2 gene expression and IL-12 induced signal transducer and activator of transcription 4 (STAT-4) activation, even when CD8 T-cell numbers from young and old mice were normalized for CD44(hi) expression. Furthermore, we demonstrate that IL-12-induced STAT-4 activation was required for T helper type 1 (Th1) cytokine-induced IFN-gamma production in CD8 T cells. These data illustrate that old mice possess a specialized subset of CD44(hi) CD8 T cells with an enhanced responsiveness to IL-12, enabling these cells to produce substantial amounts of IFN-gamma in response to Th1 cytokine stimulation. We have therefore identified a functional difference in the populations of CD44(hi) CD8 T cells from young and old mice, and believe that understanding age-associated immunological changes is essential for helping the elderly combat deadly diseases.
authors.affiliation: Center for Microbial Interface Biology, The Ohio State University, Columbus, OH 43210, USA. erin.rottinghaus@osumc.edu
authors.forename: Erin K
authors.initials: EK
authors.lastname: Rottinghaus
authors.forename: Bridget
authors.initials: B
authors.lastname: Vesosky
authors.forename: Joanne
authors.initials: J
authors.lastname: Turner
mesh_terms: D000367:Age Factors; D000375:Aging / Q000276:immunology*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D005260:Female; D018960:Hyaluronan Receptors / Q000187:drug effects / Q000378:metabolism; D007371:Interferon-gamma / Q000819:agonists / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000494:pharmacology / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D053707:Receptors, Interleukin-12 / Q000819:agonists / Q000378:metabolism; D050797:STAT4 Transcription Factor / Q000819:agonists / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*
chemical_list: C476399:Cd44 protein, mouse; D018960:Hyaluronan Receptors; D011948:Receptors, Antigen, T-Cell; D053707:Receptors, Interleukin-12; D050797:STAT4 Transcription Factor; C494091:Stat4 protein, mouse; D018664:Interleukin-12; D007371:Interferon-gamma