Antigen-independent expansion of CD28(hi) CD8 cells from aged mice: Characterization, cytokine requirements and signal transduction pathways.

Age in humans and rodents leads to immunologic defects, which include deficits in the formation of high affinity antibodies, and in responses to antigens initially encountered earlier in life. Several groups have reported that aging leads to changes in the repertoire of T cells in both mice and humans. Older human beings and mice often develop large clones of CD8 + T cells. To determine whether age alters the ability of mouse T cells to proliferate in normal hosts, we used CFSE-tagged cells to measure proliferation in vivo. We found that only memory CD8+ cells from mice older than 18 months gave measurable levels of proliferation and that the proportion of memory CD8+ T cells that proliferated in vivo increased with age. CD8 cells that proliferated in vivo contained higher levels of CD28 when compared to CD8 cells that had not divided. CD28hi CD8 + cells were preferentially able to divide in normal recipients. CD8+ T cells that divided in vivo produced INFgamma after isolation from recipient mice or their original host. In contrast, only a small percent produce IL-4 and no significant production of IL-10 was detected. Using INFgamma-receptor and IL-15 knockout mice as recipient mice we found that a response to IFNgamma from the host and IL-15 are necessary for the proliferation of CD8 + CD28hi T cells in vivo. Re-isolation of transferred CD8 cells from host mice showed that T cell activation was diminished in recovered CD8 T cells from old donors, whether they had divided in vivo or not. Cells able to proliferate in vivo could be isolated based on their unusually high levels of CD28 expression, but were found not to differ from other aged CD8 cells in their low levels of activation. These studies thus document the presence in aged mice of a population of CD28hi CD8+ cells whose ability to proliferate in vivo without antigenic stimulation and to produce IFNgamma may be involved in immune regulation. However, the abnormal in vivo proliferative responses of CD28-high CD8 cells from aged mice cannot be attributed to retention of T cell receptor responses ordinarily diminished in old age.Ph.D.Biological SciencesHealth and Environmental SciencesImmunologyMolecular biologyUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/123664/2/3096165.pd