Inhibition of tumor growth by NK1.1+ cells and CD8+ T cells activated by IL-15 through receptor beta/common gamma signaling in trans.
IL-15 is an important cytokine involved in the survival and function of CD8(+) T cells and NK cells. IL-15 can be presented by IL-15Ralpha (IL-15RA) to bind with the shared IL-2/IL-15Rbeta and common gamma-chains, which activate signaling pathways on NK cells and CD8(+) T cells. In the present study, we characterized the function of trans-presented IL-15 on NK cells and CD8(+) T cells using TC-1 tumor cells transduced with a retrovirus encoding IL-15 linked to IL-15RA (IL-15/IL-15RA). We demonstrated that the expression of IL-15/IL-15RA on TC-1 cells led to increased percentages of tumor-infiltrating NK cells, NKT cells, and CD8(+) T cells, resulting in the inhibition of tumor growth in challenged mice. Additionally, in vivo Ab depletion experiments demonstrated that NK1.1(+) cells and CD8(+) T cells were important in this inhibition of tumor growth. Furthermore, this accumulation of immune cells and inhibition of tumor growth was abolished by a single amino acid mutation in the common gamma-chain binding site on IL-15. We also observed that IL-15/IL-15RA-transduced TC-1 cells led to the activation of STAT5 in NK and CD8(+) T cells in trans, which was abolished in the mutated IL-15/IL-15RA-transduced TC-1 cells. Taken together, our data suggest that common gamma-chain binding-dependent activation of the shared IL-15/IL-2Rbeta/common gamma signaling pathway may play an important role in the activation of NK cells and CD8(+) T cells, resulting in IL-15/IL-15RA trans-presentation-mediated inhibition of tumor growth.
Rowley
Jesse
J
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21231, USA.
Monie
Archana
A
Hung
Chien-Fu
CF
Wu
T-C
TC
D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D000950:Antigens, Ly / Q000096:biosynthesis* / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006131:Growth Inhibitors / Q000096:biosynthesis / Q000502:physiology*; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics / Q000502:physiology*; D019409:Interleukin-15 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D053720:Interleukin-15 Receptor alpha Subunit / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D053646:Interleukin-2 Receptor beta Subunit / Q000502:physiology*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055651:NK Cell Lectin-Like Receptor Subfamily B / Q000096:biosynthesis* / Q000502:physiology; D010051:Ovarian Neoplasms / Q000276:immunology / Q000473:pathology / Q000517:prevention & control* / Q000821:virology; D012190:Retroviridae / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D014161:Transduction, Genetic
D000950:Antigens, Ly; D006131:Growth Inhibitors; C508022:Il2rb protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D053646:Interleukin-2 Receptor beta Subunit; C527211:Klrb1c protein, mouse; D055651:NK Cell Lectin-Like Receptor Subfamily B