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TGF-β sensitivity restrains CD8+ T cell homeostatic proliferation by enforcing sensitivity to IL-7 and IL-15.

Johnson LD, Jameson SC - PLoS ONE (2012)

Bottom Line: Previous studies found that impairing TGF-β responsiveness (through expression of a dominant-negative TGF-β RII [DNRII] transgene) leads to accumulation of memory phenotype CD8 T cells, and it was proposed that this resulted from enhanced IL-15 sensitivity.DNRII transgenic CD8 T cells still require access to self Class I MHC for homeostatic proliferation, arguing against generalized dysregulation of homeostatic cues.These findings suggest TGF-β responsiveness is critical for enforcing sensitivity to homeostatic cytokines that limit maintenance and composition of the CD8 T cell pool. (154 words).

View Article: PubMed Central - PubMed

Affiliation: Lab Medicine and Pathology, Center for Immunology, University of Minnesota, Minneapolis, Minnesota, United States of America.

ABSTRACT
The pleiotropic cytokine TGF-β has been implicated in the regulation of numerous aspects of the immune response, including naïve T cell homeostasis. Previous studies found that impairing TGF-β responsiveness (through expression of a dominant-negative TGF-β RII [DNRII] transgene) leads to accumulation of memory phenotype CD8 T cells, and it was proposed that this resulted from enhanced IL-15 sensitivity. Here we show naïve DNRII CD8 T cells exhibit enhanced lymphopenia-driven proliferation and generation of "homeostatic" memory cells. However, this enhanced response occurred in the absence of IL-15 and, unexpectedly, even in the combined absence of IL-7 and IL-15, which were thought essential for CD8 T cell homeostatic expansion. DNRII transgenic CD8 T cells still require access to self Class I MHC for homeostatic proliferation, arguing against generalized dysregulation of homeostatic cues. These findings suggest TGF-β responsiveness is critical for enforcing sensitivity to homeostatic cytokines that limit maintenance and composition of the CD8 T cell pool. (154 words).

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OT-I/DNRII homeostatically proliferate in the absence of both IL-7 and IL-15.(A,B) CFSE labeled CD44lo OT-I Rag−/− or OT-I/DNRII Rag−/− CD8 T cells were transferred into sublethally irradiated IL-7−/− x IL-15−/− hosts. After 1 week, spleens were harvested from sacrificed mice and donor cells were analyzed. (A) shows representative CFSE dilution and CD44 expression histograms for OT-I and OT-I/DNRII CD8 T cells, as indicated and (B) shows recovery of OT-I and OT-I/DNRII 1 week after transfer in the spleen (n = 3 per group). Results in (A,B) are representative of at least 3 independent experiments. (C,D) CFSE labeled CD44lo OT-I or OT-I Bim−/− CD8 T cells were transferred into sublethally irradiated IL-7−/− x IL-15−/− hosts and donor cells analyzed in the spleen 1 week later. (C) shows recovery of donor OT-I and Bim−/− OT-I CD8 T cells (n = 5), while (D) shows representative CFSE dilution histograms for these populations. The data in (C,D) are derived from two independent experiments.
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pone-0042268-g004: OT-I/DNRII homeostatically proliferate in the absence of both IL-7 and IL-15.(A,B) CFSE labeled CD44lo OT-I Rag−/− or OT-I/DNRII Rag−/− CD8 T cells were transferred into sublethally irradiated IL-7−/− x IL-15−/− hosts. After 1 week, spleens were harvested from sacrificed mice and donor cells were analyzed. (A) shows representative CFSE dilution and CD44 expression histograms for OT-I and OT-I/DNRII CD8 T cells, as indicated and (B) shows recovery of OT-I and OT-I/DNRII 1 week after transfer in the spleen (n = 3 per group). Results in (A,B) are representative of at least 3 independent experiments. (C,D) CFSE labeled CD44lo OT-I or OT-I Bim−/− CD8 T cells were transferred into sublethally irradiated IL-7−/− x IL-15−/− hosts and donor cells analyzed in the spleen 1 week later. (C) shows recovery of donor OT-I and Bim−/− OT-I CD8 T cells (n = 5), while (D) shows representative CFSE dilution histograms for these populations. The data in (C,D) are derived from two independent experiments.

Mentions: These findings lead us to consider the additional role of IL-7, which is the dominant cytokine responsible for naïve T cell homeostatic proliferation in a lymphopenic environment [18]. Mice deficient in both IL-7 and IL-15 do not support homeostatic proliferation of CD8 T cells (whether of naïve or memory phenotype), and competition for these cytokines is a major constraint of T cell proliferation in lymphopenic hosts [1]. As expected then, naïve OT-I T cells transferred into IL-7/IL-15 double knockout (DKO) animals fail to proliferate and remained of naïve phenotype (Fig. 4a), similar to earlier studies [19], [20]. Unexpectedly, however, naïve OT-I/DNRII T cells proliferated extensively in IL-7/IL-15 DKO hosts, and also converted to a CD44hi memory phenotype (Fig. 4a). One week after transfer a significant increase in OT-I/DNRII compared to OT-I was observed indicating that the OT-I/DNRII were also persisting in this environment (Fig. 4b). These data suggest that, rather than enhanced sensitivity to IL-15 (or IL-7), naïve DNRII CD8 T cells are capable of undergoing homeostatic proliferation in the complete absence of these homeostatic cytokines in the host.


TGF-β sensitivity restrains CD8+ T cell homeostatic proliferation by enforcing sensitivity to IL-7 and IL-15.

Johnson LD, Jameson SC - PLoS ONE (2012)

OT-I/DNRII homeostatically proliferate in the absence of both IL-7 and IL-15.(A,B) CFSE labeled CD44lo OT-I Rag−/− or OT-I/DNRII Rag−/− CD8 T cells were transferred into sublethally irradiated IL-7−/− x IL-15−/− hosts. After 1 week, spleens were harvested from sacrificed mice and donor cells were analyzed. (A) shows representative CFSE dilution and CD44 expression histograms for OT-I and OT-I/DNRII CD8 T cells, as indicated and (B) shows recovery of OT-I and OT-I/DNRII 1 week after transfer in the spleen (n = 3 per group). Results in (A,B) are representative of at least 3 independent experiments. (C,D) CFSE labeled CD44lo OT-I or OT-I Bim−/− CD8 T cells were transferred into sublethally irradiated IL-7−/− x IL-15−/− hosts and donor cells analyzed in the spleen 1 week later. (C) shows recovery of donor OT-I and Bim−/− OT-I CD8 T cells (n = 5), while (D) shows representative CFSE dilution histograms for these populations. The data in (C,D) are derived from two independent experiments.
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Related In: Results  -  Collection

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pone-0042268-g004: OT-I/DNRII homeostatically proliferate in the absence of both IL-7 and IL-15.(A,B) CFSE labeled CD44lo OT-I Rag−/− or OT-I/DNRII Rag−/− CD8 T cells were transferred into sublethally irradiated IL-7−/− x IL-15−/− hosts. After 1 week, spleens were harvested from sacrificed mice and donor cells were analyzed. (A) shows representative CFSE dilution and CD44 expression histograms for OT-I and OT-I/DNRII CD8 T cells, as indicated and (B) shows recovery of OT-I and OT-I/DNRII 1 week after transfer in the spleen (n = 3 per group). Results in (A,B) are representative of at least 3 independent experiments. (C,D) CFSE labeled CD44lo OT-I or OT-I Bim−/− CD8 T cells were transferred into sublethally irradiated IL-7−/− x IL-15−/− hosts and donor cells analyzed in the spleen 1 week later. (C) shows recovery of donor OT-I and Bim−/− OT-I CD8 T cells (n = 5), while (D) shows representative CFSE dilution histograms for these populations. The data in (C,D) are derived from two independent experiments.
Mentions: These findings lead us to consider the additional role of IL-7, which is the dominant cytokine responsible for naïve T cell homeostatic proliferation in a lymphopenic environment [18]. Mice deficient in both IL-7 and IL-15 do not support homeostatic proliferation of CD8 T cells (whether of naïve or memory phenotype), and competition for these cytokines is a major constraint of T cell proliferation in lymphopenic hosts [1]. As expected then, naïve OT-I T cells transferred into IL-7/IL-15 double knockout (DKO) animals fail to proliferate and remained of naïve phenotype (Fig. 4a), similar to earlier studies [19], [20]. Unexpectedly, however, naïve OT-I/DNRII T cells proliferated extensively in IL-7/IL-15 DKO hosts, and also converted to a CD44hi memory phenotype (Fig. 4a). One week after transfer a significant increase in OT-I/DNRII compared to OT-I was observed indicating that the OT-I/DNRII were also persisting in this environment (Fig. 4b). These data suggest that, rather than enhanced sensitivity to IL-15 (or IL-7), naïve DNRII CD8 T cells are capable of undergoing homeostatic proliferation in the complete absence of these homeostatic cytokines in the host.

Bottom Line: Previous studies found that impairing TGF-β responsiveness (through expression of a dominant-negative TGF-β RII [DNRII] transgene) leads to accumulation of memory phenotype CD8 T cells, and it was proposed that this resulted from enhanced IL-15 sensitivity.DNRII transgenic CD8 T cells still require access to self Class I MHC for homeostatic proliferation, arguing against generalized dysregulation of homeostatic cues.These findings suggest TGF-β responsiveness is critical for enforcing sensitivity to homeostatic cytokines that limit maintenance and composition of the CD8 T cell pool. (154 words).

View Article: PubMed Central - PubMed

Affiliation: Lab Medicine and Pathology, Center for Immunology, University of Minnesota, Minneapolis, Minnesota, United States of America.

ABSTRACT
The pleiotropic cytokine TGF-β has been implicated in the regulation of numerous aspects of the immune response, including naïve T cell homeostasis. Previous studies found that impairing TGF-β responsiveness (through expression of a dominant-negative TGF-β RII [DNRII] transgene) leads to accumulation of memory phenotype CD8 T cells, and it was proposed that this resulted from enhanced IL-15 sensitivity. Here we show naïve DNRII CD8 T cells exhibit enhanced lymphopenia-driven proliferation and generation of "homeostatic" memory cells. However, this enhanced response occurred in the absence of IL-15 and, unexpectedly, even in the combined absence of IL-7 and IL-15, which were thought essential for CD8 T cell homeostatic expansion. DNRII transgenic CD8 T cells still require access to self Class I MHC for homeostatic proliferation, arguing against generalized dysregulation of homeostatic cues. These findings suggest TGF-β responsiveness is critical for enforcing sensitivity to homeostatic cytokines that limit maintenance and composition of the CD8 T cell pool. (154 words).

Show MeSH
Related in: MedlinePlus