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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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Homeostatic proliferation of OT-I/DNRII is MHC I dependent.CFSE labeled CD44lo OT-I Rag−/− or OT-I/DNRII Rag−/− CD8 T cells were transferred into irradiated KbDb−/− or wild-type hosts. One week later, lymph nodes and spleen from sacrificed mice were pooled and analyzed. (A) Representative CFSE dilution histograms of OT-I and OT-I/DNRII CD8 T cells in pooled lymph nodes and spleen one week after transfer into irradiated B6 and KbDb−/− hosts. (B) Recovery of OT-I and OT-I/DNRII CD8 T cells after one week in irradiated B6 or KbDb−/− hosts. Each symbol represents an individual mouse. Results are presented as the combination of three independent experiments.
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pone-0042268-g005: Homeostatic proliferation of OT-I/DNRII is MHC I dependent.CFSE labeled CD44lo OT-I Rag−/− or OT-I/DNRII Rag−/− CD8 T cells were transferred into irradiated KbDb−/− or wild-type hosts. One week later, lymph nodes and spleen from sacrificed mice were pooled and analyzed. (A) Representative CFSE dilution histograms of OT-I and OT-I/DNRII CD8 T cells in pooled lymph nodes and spleen one week after transfer into irradiated B6 and KbDb−/− hosts. (B) Recovery of OT-I and OT-I/DNRII CD8 T cells after one week in irradiated B6 or KbDb−/− hosts. Each symbol represents an individual mouse. Results are presented as the combination of three independent experiments.

Mentions: To this point, our data suggested that diminished TGF-β sensitivity released naïve CD8 T cells from the normal cytokine restraints on homeostatic proliferation. However, interaction with self-pMHC molecules is also important in supporting naïve (but not memory) CD8 T cell HP [16]. To test whether DNRII CD8 T cells were independent of self MHC Class I for homeostatic proliferation in vivo, we transferred low numbers of CFSE labeled CD44lo OT-I or OT-I/DNRII CD8 T cells into irradiated KbDb deficient mice. As expected, OT-I T cells failed to undergo HP in the Class I MHC-deficient environment showing no CFSE dilution or expansion in stark comparison to their response in irradiated wild-type hosts (Fig. 5). Interestingly, naïve OT-I/DNRII CD8 T cells also failed to expand in Class I MHC deficient hosts (Fig. 5), indicating that altered TGF-β sensitivity does not alter requirement for perception of self MHC molecules in driving homeostatic proliferation. Taken together with the co-transfer studies (Fig. 2 and S2), this suggests that OT-I/DNRII may out compete OT-I for MHC I interaction resulting in the enhanced expansion of OT-I/DNRII. This might suggest enhanced sensitivity of DNRII T cells for TCR stimuli: However, when we assessed naïve OT-I and OT-I/DNRII cells for sensitivity to high and low affinity TCR ligands we found no substantial difference in their short term in vitro reactivity (Fig. S5). Whether DNRII CD8 T cells show increased sensitivity to self peptide/MHC ligands encountered in vivo is difficult to test directly.


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)

Homeostatic proliferation of OT-I/DNRII is MHC I dependent.CFSE labeled CD44lo OT-I Rag−/− or OT-I/DNRII Rag−/− CD8 T cells were transferred into irradiated KbDb−/− or wild-type hosts. One week later, lymph nodes and spleen from sacrificed mice were pooled and analyzed. (A) Representative CFSE dilution histograms of OT-I and OT-I/DNRII CD8 T cells in pooled lymph nodes and spleen one week after transfer into irradiated B6 and KbDb−/− hosts. (B) Recovery of OT-I and OT-I/DNRII CD8 T cells after one week in irradiated B6 or KbDb−/− hosts. Each symbol represents an individual mouse. Results are presented as the combination of three independent experiments.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3412850&req=5

pone-0042268-g005: Homeostatic proliferation of OT-I/DNRII is MHC I dependent.CFSE labeled CD44lo OT-I Rag−/− or OT-I/DNRII Rag−/− CD8 T cells were transferred into irradiated KbDb−/− or wild-type hosts. One week later, lymph nodes and spleen from sacrificed mice were pooled and analyzed. (A) Representative CFSE dilution histograms of OT-I and OT-I/DNRII CD8 T cells in pooled lymph nodes and spleen one week after transfer into irradiated B6 and KbDb−/− hosts. (B) Recovery of OT-I and OT-I/DNRII CD8 T cells after one week in irradiated B6 or KbDb−/− hosts. Each symbol represents an individual mouse. Results are presented as the combination of three independent experiments.
Mentions: To this point, our data suggested that diminished TGF-β sensitivity released naïve CD8 T cells from the normal cytokine restraints on homeostatic proliferation. However, interaction with self-pMHC molecules is also important in supporting naïve (but not memory) CD8 T cell HP [16]. To test whether DNRII CD8 T cells were independent of self MHC Class I for homeostatic proliferation in vivo, we transferred low numbers of CFSE labeled CD44lo OT-I or OT-I/DNRII CD8 T cells into irradiated KbDb deficient mice. As expected, OT-I T cells failed to undergo HP in the Class I MHC-deficient environment showing no CFSE dilution or expansion in stark comparison to their response in irradiated wild-type hosts (Fig. 5). Interestingly, naïve OT-I/DNRII CD8 T cells also failed to expand in Class I MHC deficient hosts (Fig. 5), indicating that altered TGF-β sensitivity does not alter requirement for perception of self MHC molecules in driving homeostatic proliferation. Taken together with the co-transfer studies (Fig. 2 and S2), this suggests that OT-I/DNRII may out compete OT-I for MHC I interaction resulting in the enhanced expansion of OT-I/DNRII. This might suggest enhanced sensitivity of DNRII T cells for TCR stimuli: However, when we assessed naïve OT-I and OT-I/DNRII cells for sensitivity to high and low affinity TCR ligands we found no substantial difference in their short term in vitro reactivity (Fig. S5). Whether DNRII CD8 T cells show increased sensitivity to self peptide/MHC ligands encountered in vivo is difficult to test directly.

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