Reversible Defects in Natural Killer and Memory Cd8 T Cell Lineages in Interleukin 15–Deficient Mice

By M. Kennedy, M. Glaccum, Sandra N. Brown, E. Butz, J. Viney, M. Embers, N. Matsuki, K. Charrier, Lisa M Sedger, C. Willis and 6 more. Journal of Experimental Medicine, 2000

1,808 citations recorded by the source corpus.

C57BL/6 mice genetically deficient in interleukin 15 (IL-15−/− mice) were generated by gene targeting. IL-15−/− mice displayed marked reductions in numbers of thymic and peripheral natural killer (NK) T cells, memory phenotype CD8+ T cells, and distinct subpopulations of intestinal intraepithelial lymphocytes (IELs). The reduction but not absence of these populations in IL-15−/− mice likely reflects an important role for IL-15 for expansion and/or survival of these cells. IL-15−/− mice lacked NK cells, as assessed by both immunophenotyping and functional criteria, indicating an obligate role for IL-15 in the development and functional maturation of NK cells. Specific defects associated with IL-15 deficiency were reversed by in vivo administration of exogenous IL-15. Despite their immunological defects, IL-15−/− mice remained healthy when maintained under specific pathogen-free conditions. However, IL-15−/− mice are likely to have compromised host defense responses to various pathogens, as they were unable to mount a protective response to challenge with vaccinia virus. These data reveal critical roles for IL-15 in the development of specific lymphoid lineages. Moreover, the ability to rescue lymphoid defects in IL-15−/− mice by IL-15 administration represents a powerful means by which to further elucidate the biological roles of this cytokine.

Subfields: Hematology, Immunology

View Paper: https://www.semanticscholar.org/paper/41e180bc8072463942265237722bbbad03245ac6

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Rafi Ahmed
2. E. Wherry
3. S. Kaech
4. M. Bevan
5. C. Surh
6. Erika L. Pearce
7. S. Rosenberg
8. N. Restifo

Citations in the corpus

• Redistribution, hyperproliferation, activation of natural killer cells and CD8 T cells, and cytokine production during first-in-human clinical trial of recombinant human interleukin-15 in patients with cancer. (2015, background): “However, in many adaptive immune responses, IL-2 and IL-15 have distinct roles.(8,12-16) In contrast to IL-2, IL-15 inhibited IL-2–mediated AICD, less consistently activated Tregs, and did not cause a significant capillary leak syndrome in mice or nonhuman primates (NHPs).”
• Cytokine Requirements for Acute and Basal Homeostatic Proliferation of Naive and Memory CD8+ T Cells (2002, background): “IL-15–deficient (IL-15 / , B6 background) mice (26) were bred”
• An IFN-γ-Dependent Pathway Controls Stimulation of Memory Phenotype CD8+ T Cell Turnover In Vivo by IL-12, IL-18, and IFN-γ1 (2001, background): “both the IFN-I-dependent and IFNg-dependent pathways of in vivo T cell proliferation will not operate in IL-15 2/2 mice (29).”
• T-bet regulates the terminal maturation and homeostasis of NK and Valpha14i NKT cells. (2004, background): “Radio-resistant BM cells proSummary ducing IL-15 are critical for NK cell development and homeostasis (Kennedy et al., 2000; Ranson et al., Natural killer (NK) and CD1d-restricted V 14i natural 2003b).”
• RORγt and commensal microflora are required for the differentiation of mucosal interleukin 22–producing NKp46+ cells (2009, background): “Reflective of the involvement of IL-15 in promoting the development and survival of NK cells, Il15 −/− mice have fewer NK cells in the peripher”
• Reduced Expression of Bcl-2 in CD8+ T Cells Deficient in the IL-15 Receptor α-Chain1 (2002, methodology): “Although the percentage of CD8 single-positive (SP) thymocytes was reduced by 45% in young IL-15R / mice (16), the number and composition of thymocytes appeared to be normal in adult IL-15 / mice (17).”
• Cutting Edge: Requirement for IL-15 in the Generation of Primary and Memory Antigen-Specific CD8 T Cells1 (2002, background): “Whereas both IL-15 and IL-15R are required for the generation of CD44CD8 T cells (8, 9), we asked whether there was a similar requirement for generation of primary Ag-specific CD44CD8 T cells in response to an infection.”
• Cutting Edge: Murine Dendritic Cells Require IL-15Rα to Prime NK Cells1 (2004, background): “15R is required for IL-15 signals (8, 9).”