Cutting Edge: Requirement for IL-15 in the Generation of Primary and Memory Antigen-Specific CD8 T Cells

Abstract

IL-15 and IL-15Rα are required for generation of memory-phenotype CD8 T cells in unimmunized mice. However, the role of IL-15 in primary expansion and generation of Ag-specific memory CD8 T cells in vivo has not been investigated. We characterized the CD8 T cell response against vesicular stomatitis virus (VSV) in IL-15−/− and IL-15Rα−/− mice. Surprisingly, IL-15 was required for primary expansion of VSV-specific CD8 T cells. The generation of VSV-specific memory CD8 T cells was also impaired without IL-15 signaling, and this defect correlated with a decrease in memory CD8 T cell turnover. Despite minimal proliferation without IL-15, a subset of memory cells survived long-term. IL-15Rα expression was low on naive CD8 T cells, up-regulated on Ag-specific effector cells, and sustained on memory cells. Thus, IL-15 was important for the generation and the subsequent maintenance of antiviral memory CD8 T cells.

Interleukin‐15 mediates protection against experimental tuberculosis: A role for NKG2D‐dependent effector mechanisms of CD8+ T cells

“…Previous work has also shown that under certain conditions only long-term maintenance of effector/memory-phenotype CD44 high CD8 + T cells is controlled by IL-15 [20]. After infection with VSV, the clonal expansion of tetramer-positive VSV-specific CD8 + T cells was strikingly decreased in IL-15 -/-mice [41].…”

“…In accordance with the importance of CD8 + T cells for protection against a number of pathogens, IL-15 was shown to improve the proliferation of memory/effector CD8 + T cells and protective CD8 + T cell-mediated immune responses such as IFN-c production and cytotoxicity [37][38][39]. For example, a deficiency in IL-15 or IL-15Ra led to an impaired CD8 + T cell-mediated immune response and decreased protection from infection with herpes simplex virus type 2 [21,40], vesicular stomatitis virus (VSV) [41], vaccinia virus [18] or Toxoplasma gondii [42]. However, in some cases the role of IL-15 appeared to be redundant since IL-15 -/-mice proved capable of developing protective immune responses after infection with gamma herpes virus 68 [43], lymphocytic choriomeningitis virus [20] or T. gondii [44].…”

“…Maintenance of CD8 + T cells is critically dependent upon the two common c chain cytokines IL-7 and IL-15. Whereas IL-7 promotes the survival of both naive and memory CD8 + T cells, IL-15 uniquely supports basal memory CD8 + T cell proliferation [20,41,48]. Thus, in the absence of proliferative IL-15 signals, effector/memory CD8 + T cells undergo slow atrophy in number until they become essentially undetectable under certain conditions [20,49].…”

“…Previous work has also shown that under certain conditions only long-term maintenance of effector/memory-phenotype CD44 high CD8 + T cells is controlled by . After infection with VSV, the clonal expansion of tetramer-positive VSV-specific CD8 + T cells was strikingly decreased in IL-15 -/-mice [41]. However, during Mtb infection of IL-15 -/-mice, the significantly reduced accumulation of CD8 + T cells was not limited to CD44 high CD8 + T cells expressing an effector/memory phenotype.…”

The role of apoptosis in the development and function of T lymphocytes

“…It is believed that CD8 + memory T cells can persist without MHC class I [209]. However, CD8 + memory T cell survival depends on IL-15 in a normal host, and also depends on IL-7 in a lymphopenic host or in an IL-15 deficient host [169,[210][211][212][213]. CD4 + memory T cell survival and homeostatic proliferation depend on IL-7 signal and also require TCR/MHC class II interaction.…”