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Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice.

Kennedy MK, Glaccum M, Brown SN, Butz EA, Viney JL, Embers M, Matsuki N, Charrier K, Sedger L, Willis CR, Brasel K, Morrissey PJ, Stocking K, Schuh JC, Joyce S, Peschon JJ - J. Exp. Med. (2000)

Bottom Line: 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).Specific defects associated with IL-15 deficiency were reversed by in vivo administration of exogenous IL-15.These data reveal critical roles for IL-15 in the development of specific lymphoid lineages.

View Article: PubMed Central - PubMed

Affiliation: Immunex Corporation, Seattle, Washington 98101, USA.

ABSTRACT
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.

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IL-15−/− mice have normal numbers of conventional T cells but reduced numbers of thymic NK T cells. (A) Thymocytes from individual male IL-15+/− (left) or IL-15−/− (right) littermates were analyzed for expression of CD4 and CD8 (n = 2/group; 12–13 wk of age). The numbers shown represent the percentages of cells within each quadrant. The thymic cellularity was similar in both groups. The results shown are representative of three experiments. (B) NK T cell populations of thymocytes (top), intrahepatic mononuclear cells (middle), and splenocytes (bottom) from individual C57BL/6 or IL-15−/− mice. Live gating of the HSAlowCD8low thymocyte population was used to acquire data on CD44hiNK1.1+ or CD44hiTCR Vβ8+ thymocytes. Similarly, live gating of B220 splenocytes was used to acquire data on NK1.1+TCR-β+ splenic NK T cells. The numbers shown represent the percentage of cells with an NK T cell phenotype. (C) Absolute numbers of thymic NK T populations in control and IL-15−/− mice. The numbers shown represent the mean absolute number ± SEM of thymic NK T cell populations from C57BL/6 or IL-15−/− mice (n = 3/group). NK T cell numbers were calculated from the percentages of HSAlow CD8low thymocytes that were Ly6Chi NK1.1+ or CD44hi and NK1.1+, TCR-α/β+, or Vβ8.1,8.2+. The results shown are representative of two experiments.
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Figure 3: IL-15−/− mice have normal numbers of conventional T cells but reduced numbers of thymic NK T cells. (A) Thymocytes from individual male IL-15+/− (left) or IL-15−/− (right) littermates were analyzed for expression of CD4 and CD8 (n = 2/group; 12–13 wk of age). The numbers shown represent the percentages of cells within each quadrant. The thymic cellularity was similar in both groups. The results shown are representative of three experiments. (B) NK T cell populations of thymocytes (top), intrahepatic mononuclear cells (middle), and splenocytes (bottom) from individual C57BL/6 or IL-15−/− mice. Live gating of the HSAlowCD8low thymocyte population was used to acquire data on CD44hiNK1.1+ or CD44hiTCR Vβ8+ thymocytes. Similarly, live gating of B220 splenocytes was used to acquire data on NK1.1+TCR-β+ splenic NK T cells. The numbers shown represent the percentage of cells with an NK T cell phenotype. (C) Absolute numbers of thymic NK T populations in control and IL-15−/− mice. The numbers shown represent the mean absolute number ± SEM of thymic NK T cell populations from C57BL/6 or IL-15−/− mice (n = 3/group). NK T cell numbers were calculated from the percentages of HSAlow CD8low thymocytes that were Ly6Chi NK1.1+ or CD44hi and NK1.1+, TCR-α/β+, or Vβ8.1,8.2+. The results shown are representative of two experiments.

Mentions: The relative proportions and absolute numbers of double positive CD4+CD8+ immature thymocytes and single positive CD4+ or CD8+ mature thymocytes were similar in control and IL-15−/− mice (Fig. 3 A, and data not shown). Thus, conventional thymic T cell development appeared normal in IL-15−/− mice. In contrast, the relative proportion and absolute numbers of thymic NK T cells were significantly reduced in IL-15−/− mice compared with controls (Fig. 3b and Fig. c). Decreases in the relative proportions and absolute numbers of NK T cells were also observed in the spleen and liver of IL-15−/− mice (Fig. 3 B, and data not shown).


Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice.

Kennedy MK, Glaccum M, Brown SN, Butz EA, Viney JL, Embers M, Matsuki N, Charrier K, Sedger L, Willis CR, Brasel K, Morrissey PJ, Stocking K, Schuh JC, Joyce S, Peschon JJ - J. Exp. Med. (2000)

IL-15−/− mice have normal numbers of conventional T cells but reduced numbers of thymic NK T cells. (A) Thymocytes from individual male IL-15+/− (left) or IL-15−/− (right) littermates were analyzed for expression of CD4 and CD8 (n = 2/group; 12–13 wk of age). The numbers shown represent the percentages of cells within each quadrant. The thymic cellularity was similar in both groups. The results shown are representative of three experiments. (B) NK T cell populations of thymocytes (top), intrahepatic mononuclear cells (middle), and splenocytes (bottom) from individual C57BL/6 or IL-15−/− mice. Live gating of the HSAlowCD8low thymocyte population was used to acquire data on CD44hiNK1.1+ or CD44hiTCR Vβ8+ thymocytes. Similarly, live gating of B220 splenocytes was used to acquire data on NK1.1+TCR-β+ splenic NK T cells. The numbers shown represent the percentage of cells with an NK T cell phenotype. (C) Absolute numbers of thymic NK T populations in control and IL-15−/− mice. The numbers shown represent the mean absolute number ± SEM of thymic NK T cell populations from C57BL/6 or IL-15−/− mice (n = 3/group). NK T cell numbers were calculated from the percentages of HSAlow CD8low thymocytes that were Ly6Chi NK1.1+ or CD44hi and NK1.1+, TCR-α/β+, or Vβ8.1,8.2+. The results shown are representative of two experiments.
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Figure 3: IL-15−/− mice have normal numbers of conventional T cells but reduced numbers of thymic NK T cells. (A) Thymocytes from individual male IL-15+/− (left) or IL-15−/− (right) littermates were analyzed for expression of CD4 and CD8 (n = 2/group; 12–13 wk of age). The numbers shown represent the percentages of cells within each quadrant. The thymic cellularity was similar in both groups. The results shown are representative of three experiments. (B) NK T cell populations of thymocytes (top), intrahepatic mononuclear cells (middle), and splenocytes (bottom) from individual C57BL/6 or IL-15−/− mice. Live gating of the HSAlowCD8low thymocyte population was used to acquire data on CD44hiNK1.1+ or CD44hiTCR Vβ8+ thymocytes. Similarly, live gating of B220 splenocytes was used to acquire data on NK1.1+TCR-β+ splenic NK T cells. The numbers shown represent the percentage of cells with an NK T cell phenotype. (C) Absolute numbers of thymic NK T populations in control and IL-15−/− mice. The numbers shown represent the mean absolute number ± SEM of thymic NK T cell populations from C57BL/6 or IL-15−/− mice (n = 3/group). NK T cell numbers were calculated from the percentages of HSAlow CD8low thymocytes that were Ly6Chi NK1.1+ or CD44hi and NK1.1+, TCR-α/β+, or Vβ8.1,8.2+. The results shown are representative of two experiments.
Mentions: The relative proportions and absolute numbers of double positive CD4+CD8+ immature thymocytes and single positive CD4+ or CD8+ mature thymocytes were similar in control and IL-15−/− mice (Fig. 3 A, and data not shown). Thus, conventional thymic T cell development appeared normal in IL-15−/− mice. In contrast, the relative proportion and absolute numbers of thymic NK T cells were significantly reduced in IL-15−/− mice compared with controls (Fig. 3b and Fig. c). Decreases in the relative proportions and absolute numbers of NK T cells were also observed in the spleen and liver of IL-15−/− mice (Fig. 3 B, and data not shown).

Bottom Line: 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).Specific defects associated with IL-15 deficiency were reversed by in vivo administration of exogenous IL-15.These data reveal critical roles for IL-15 in the development of specific lymphoid lineages.

View Article: PubMed Central - PubMed

Affiliation: Immunex Corporation, Seattle, Washington 98101, USA.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus