IL-15 as a mediator of CD4+ help for CD8+ T cell longevity and avoidance of TRAIL-mediated apoptosis
- SangKon Oh*,†,
- Liyanage P. Perera‡,
- Masaki Terabe*,
- Ling Ni§,
- Thomas A. Waldmann‡,¶, and
- Jay A. Berzofsky*,¶
- *Vaccine Branch and
- ‡Metabolism Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1578; and
- §Baylor Institute for Immunology Research, Baylor University Medical Center, Dallas, TX 75204
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Contributed by Thomas A. Waldmann, January 31, 2008 (received for review December 20, 2007)
Abstract
CD4+ helper T cells contribute to the induction and maintenance of antigen-specific CD8+ T cells. Their absence results in short-lived antigen-specific CD8+ T cells and defective secondary CD8+ T cell responses because of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis. Here, we show that IL-15 codelivered with vaccines can overcome CD4+ T cell deficiency for promoting longevity of antigen-specific CD8+ T cells and avoidance of TRAIL-mediated apoptosis. In both priming and secondary responses, IL-15 down-regulates proapoptotic Bax, an intermediate in TRAIL-mediated apoptosis, and increases anti-apoptotic Bcl-XL in CD8+ T cells. Thus, IL-15 is sufficient to mimic CD4+ T cell help. Antigen-specific CD4+ T cells induce dendritic cells (DCs) to produce IL-15. IL-15 is also necessary for optimal help, because helper cells do not deliver effective help through IL-15−/− DCs. Therefore, IL-15 codelivered with vaccines can overcome CD4+ helper T cell deficiency for induction of functionally efficient CD8+ T cells and maintenance of CD8+ cytotoxic T lymphocytes (CTLs), and IL-15 is probably one of the natural mediators of help. These findings suggest new vaccine strategies against infections and cancers, especially in individuals with CD4-deficiency.
Footnotes
- ¶To whom correspondence may be addressed. E-mail: tawald{at}helix.nih.gov or berzofsk{at}helix.nih.gov
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Author contributions: S.O., L.P.P., M.T., T.A.W., and J.A.B. designed research; S.O., L.P.P., M.T., and L.N. performed research; S.O., L.P.P., M.T., and J.A.B. analyzed data; and S.O., T.A.W., and J.A.B. wrote the paper.
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↵ †Present address: Baylor Institute for Immunology Research, Baylor University Medical Center, 3434 Live Oak Street, Dallas, TX 75204.
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The authors declare no conflict of interest.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0801003105/DCSupplemental.
- © 2008 by The National Academy of Sciences of the USA
