Role of IL-15 as a growth factor and activator for memory CD8 T cells: Memory T lymphocytes, arising from naive T lymphocytes after antigenic stimulation and being long-lived, are the cellular basis for immunological memory. Recent studies of CD8 T cells suggest that generation of CD8 memory T cells requires the engagement of TCR with antigen yet the maintenance of CD8 memory T cells appears to be dependent on cytokines, such as IL-15, independent of TCR. Although considerable progresses have been made in understanding the molecular and cellular events of TCR induced differentiation and proliferation in the past decade, less is known about the mechanisms of IL-15 action. In an effort to analyze the molecular and cellular changes induced by IL-15, and to compare IL-15- and TCR-mediated stimulation, we recently conducted a parallel comparitive analysis of genome-scale gene expression, proliferation, effector molecule production, and cytotoxicity in memory phenotype CD8 T cells stimulated in vitro with IL-15 or anti-CD3 mAb. Our study reveals several interesting and unexpected findings. We have identified 207 cDNA clones whose expression levels were significantly changed (at least 2-fold) in memory phenotype CD8 T cells after IL-15 and/or anti-CD3 stimulation. Approximately, 76% of those cDNA clones exhibited a similar pattern of changes with either IL-15 or anti-CD3 treatment. Furthermore, memory phenotype CD8+ T cells exhibited similar degree of cellular proliferation; production of effector molecules (IFNg, TNFb, granzyme B and perforin), and cytotoxicity in response to TCR or IL-15 mediated stimulations. These findings provide molecular evidence of IL-15 mediated events in memory phenotype CD8 T cells, and suggest IL-15 mimics TCR crosslinking induced gene expression, proliferation, and cytotoxic effector functions. Despite a remarkable resemblance of the action of IL-15 and TCR crosslinking, we have identified differences between these two stimulations in gene expression: 32 cDNA clones are uniquely regulated in response to IL-15, and 17 clones are unique to anti-CD3 treatment. Furthermore, analysis of protein levels of the differentially expressed surface activation markers confirmed differential increase in CD53 expression by IL-15 and differential increase of CD2 expression by anti-CD3 treated in memory CD8+ T cells. Taken together, these results indicate that IL-15 not only promotes survival but also activates the effector function of memory phenotype CD8+ T cells.
