Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 105, Issue 13, Pages 5201-5206Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0801003105
Keywords
cytotoxic T lymphocytes; T cell help
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Funding
- NATIONAL CANCER INSTITUTE [Z01SC004020, Z01SC004002, ZIASC004020, ZIASC004002] Funding Source: NIH RePORTER
- Intramural NIH HHS Funding Source: Medline
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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-X-L 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.
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