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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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Lymphoid organ weights and cellularity. Average values are indicated by the horizontal lines. Significant differences in organ weights or cellularity between groups are indicated with asterisks. (A) Weights of individual spleens or thymi from 10–12.5-wk-old male IL-15+/− or IL-15−/− mice (n = 17–18/group). (B) Total weight of six peripheral LNs (two each of proper axillary, accessory axillary, and inguinal) from individual 10–12.5-wk-old male IL-15+/− or IL-15−/− mice (n = 17–18/group). *P < 0.05 (Student's t test). (C and D) Cellularity data were collected in multiple experiments, each of which used age- and sex-matched mice. The values shown are from both male and female mice between 9 and 20 wk of age. Control mice included IL-15+/− littermates (used in the majority of cases), IL-15+/+ littermates, and C57BL/6 mice. The average number of cells per LN was calculated from the combined cellularity of the six LNs described above. **P < 0.005 (mixed models analysis of variance).
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Figure 2: Lymphoid organ weights and cellularity. Average values are indicated by the horizontal lines. Significant differences in organ weights or cellularity between groups are indicated with asterisks. (A) Weights of individual spleens or thymi from 10–12.5-wk-old male IL-15+/− or IL-15−/− mice (n = 17–18/group). (B) Total weight of six peripheral LNs (two each of proper axillary, accessory axillary, and inguinal) from individual 10–12.5-wk-old male IL-15+/− or IL-15−/− mice (n = 17–18/group). *P < 0.05 (Student's t test). (C and D) Cellularity data were collected in multiple experiments, each of which used age- and sex-matched mice. The values shown are from both male and female mice between 9 and 20 wk of age. Control mice included IL-15+/− littermates (used in the majority of cases), IL-15+/+ littermates, and C57BL/6 mice. The average number of cells per LN was calculated from the combined cellularity of the six LNs described above. **P < 0.005 (mixed models analysis of variance).

Mentions: Within the course of these studies, we noted no consistent or marked difference in the size or the cellularity of the spleens, thymi, or peripheral LNs between small groups of age- and sex-matched IL-15−/− and littermate control (either IL-15+/+ or IL-15+/−) mice. To compare the groups in a quantitative fashion, the lymphoid organs were removed and weighed from a cohort of age-matched male mice (n = 17–18/group). There were no significant differences in the average absolute weights or organ to body weight ratios of the spleens or thymi between IL-15−/− and their heterozygote littermate controls (Fig. 2 A, and data not shown). However, the average absolute weight and organ to body weight ratio of the peripheral LNs from IL-15−/− mice were significantly lower than those of the controls (Fig. 2 B, and data not shown). To compare cellularity of these organs, data were pooled from numerous experiments. Although groups of mice were age and sex matched within each experiment, the pooled data samples were derived from both male and female mice between 9 and 20 wk of age (Fig. 2C and Fig. D). The pooled data revealed a significant decrease in the average cellularity of the peripheral LNs, but not the spleen or thymi, between IL-15−/− mice and the controls.


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)

Lymphoid organ weights and cellularity. Average values are indicated by the horizontal lines. Significant differences in organ weights or cellularity between groups are indicated with asterisks. (A) Weights of individual spleens or thymi from 10–12.5-wk-old male IL-15+/− or IL-15−/− mice (n = 17–18/group). (B) Total weight of six peripheral LNs (two each of proper axillary, accessory axillary, and inguinal) from individual 10–12.5-wk-old male IL-15+/− or IL-15−/− mice (n = 17–18/group). *P < 0.05 (Student's t test). (C and D) Cellularity data were collected in multiple experiments, each of which used age- and sex-matched mice. The values shown are from both male and female mice between 9 and 20 wk of age. Control mice included IL-15+/− littermates (used in the majority of cases), IL-15+/+ littermates, and C57BL/6 mice. The average number of cells per LN was calculated from the combined cellularity of the six LNs described above. **P < 0.005 (mixed models analysis of variance).
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Related In: Results  -  Collection

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Figure 2: Lymphoid organ weights and cellularity. Average values are indicated by the horizontal lines. Significant differences in organ weights or cellularity between groups are indicated with asterisks. (A) Weights of individual spleens or thymi from 10–12.5-wk-old male IL-15+/− or IL-15−/− mice (n = 17–18/group). (B) Total weight of six peripheral LNs (two each of proper axillary, accessory axillary, and inguinal) from individual 10–12.5-wk-old male IL-15+/− or IL-15−/− mice (n = 17–18/group). *P < 0.05 (Student's t test). (C and D) Cellularity data were collected in multiple experiments, each of which used age- and sex-matched mice. The values shown are from both male and female mice between 9 and 20 wk of age. Control mice included IL-15+/− littermates (used in the majority of cases), IL-15+/+ littermates, and C57BL/6 mice. The average number of cells per LN was calculated from the combined cellularity of the six LNs described above. **P < 0.005 (mixed models analysis of variance).
Mentions: Within the course of these studies, we noted no consistent or marked difference in the size or the cellularity of the spleens, thymi, or peripheral LNs between small groups of age- and sex-matched IL-15−/− and littermate control (either IL-15+/+ or IL-15+/−) mice. To compare the groups in a quantitative fashion, the lymphoid organs were removed and weighed from a cohort of age-matched male mice (n = 17–18/group). There were no significant differences in the average absolute weights or organ to body weight ratios of the spleens or thymi between IL-15−/− and their heterozygote littermate controls (Fig. 2 A, and data not shown). However, the average absolute weight and organ to body weight ratio of the peripheral LNs from IL-15−/− mice were significantly lower than those of the controls (Fig. 2 B, and data not shown). To compare cellularity of these organs, data were pooled from numerous experiments. Although groups of mice were age and sex matched within each experiment, the pooled data samples were derived from both male and female mice between 9 and 20 wk of age (Fig. 2C and Fig. D). The pooled data revealed a significant decrease in the average cellularity of the peripheral LNs, but not the spleen or thymi, between IL-15−/− mice and the controls.

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