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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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IL-15 is not required for the enhanced homeostatic proliferation of OT-I/DNRII CD8 T cells.CFSE labeled CD44lo OT-I and OT-I/DNRII CD8 T cells were adoptively transferred into sublethally irradiated IL-15−/− hosts. Host animals were sacrificed and donor cells were analyzed. (A) CFSE dilution of OT-I and OT-I/DNRII CD8 T cells in the spleen 3 weeks after co-transfer into sub-lethally irradiated B6 and IL-15 KO hosts (n = 3). (B) Recovery of OT-I and OT-I/DNRII CD8 T cells 18 days after single or co-transfer in the lymph nodes (n = 3). Data are representative of at least 3 independent experiments.
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pone-0042268-g003: IL-15 is not required for the enhanced homeostatic proliferation of OT-I/DNRII CD8 T cells.CFSE labeled CD44lo OT-I and OT-I/DNRII CD8 T cells were adoptively transferred into sublethally irradiated IL-15−/− hosts. Host animals were sacrificed and donor cells were analyzed. (A) CFSE dilution of OT-I and OT-I/DNRII CD8 T cells in the spleen 3 weeks after co-transfer into sub-lethally irradiated B6 and IL-15 KO hosts (n = 3). (B) Recovery of OT-I and OT-I/DNRII CD8 T cells 18 days after single or co-transfer in the lymph nodes (n = 3). Data are representative of at least 3 independent experiments.

Mentions: Lymphopenia-induced proliferation of naïve CD8 T cells is driven by signals through both the TCR (engaging self peptide/MHC ligands) and the cytokines IL-7 and IL-15. Indeed, it was proposed that TGF-β signaling attenuates the memory CD8 T cell response to IL-15 by impairing CD122 expression [14] and, in keeping with this, TGF-β RII-deficient CD4 T cells were shown to exhibit CD122 upregulation suggesting increased IL-15 sensitivity [4]. On the other hand, our studies did not indicate a marked change in CD122 expression in naïve OT-I/DNRII (Fig. 1a) or during HP (Fig. 1b). To explore this model further, we transferred naïve OT-I and OT-I/DNRII CD8 T cells (together or separately) into sub-lethally irradiated IL-15 deficient hosts. As we reported previously, lack of IL-15 in the lymphopenic host leads to reduced expansion of OT-I cells at late stages of the response [17] and this was observed for both WT and DNRII OT-I cells (Fig. 3 and S2). However, OT-I/DNRII T cells still exhibited an advantage compared to their WT counterparts in the IL-15-deficient hosts, as measured by both their proliferation (Fig. 3a) and accumulation (Fig. 3b). As was observed with B6 hosts, OT-I/DNRII had an even greater advantage in situations where OT-I and OT-I/DNRII cells were co-transferred into the same IL-15−/− recipients (Fig. 3b and S2). Together, these data indicate that the competitive advantage of the DNRII pool during HP is not solely due to improved IL-15 sensitivity (although IL-15 enhances the proliferative response of both WT and DNRII populations).


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)

IL-15 is not required for the enhanced homeostatic proliferation of OT-I/DNRII CD8 T cells.CFSE labeled CD44lo OT-I and OT-I/DNRII CD8 T cells were adoptively transferred into sublethally irradiated IL-15−/− hosts. Host animals were sacrificed and donor cells were analyzed. (A) CFSE dilution of OT-I and OT-I/DNRII CD8 T cells in the spleen 3 weeks after co-transfer into sub-lethally irradiated B6 and IL-15 KO hosts (n = 3). (B) Recovery of OT-I and OT-I/DNRII CD8 T cells 18 days after single or co-transfer in the lymph nodes (n = 3). Data are representative of at least 3 independent experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3412850&req=5

pone-0042268-g003: IL-15 is not required for the enhanced homeostatic proliferation of OT-I/DNRII CD8 T cells.CFSE labeled CD44lo OT-I and OT-I/DNRII CD8 T cells were adoptively transferred into sublethally irradiated IL-15−/− hosts. Host animals were sacrificed and donor cells were analyzed. (A) CFSE dilution of OT-I and OT-I/DNRII CD8 T cells in the spleen 3 weeks after co-transfer into sub-lethally irradiated B6 and IL-15 KO hosts (n = 3). (B) Recovery of OT-I and OT-I/DNRII CD8 T cells 18 days after single or co-transfer in the lymph nodes (n = 3). Data are representative of at least 3 independent experiments.
Mentions: Lymphopenia-induced proliferation of naïve CD8 T cells is driven by signals through both the TCR (engaging self peptide/MHC ligands) and the cytokines IL-7 and IL-15. Indeed, it was proposed that TGF-β signaling attenuates the memory CD8 T cell response to IL-15 by impairing CD122 expression [14] and, in keeping with this, TGF-β RII-deficient CD4 T cells were shown to exhibit CD122 upregulation suggesting increased IL-15 sensitivity [4]. On the other hand, our studies did not indicate a marked change in CD122 expression in naïve OT-I/DNRII (Fig. 1a) or during HP (Fig. 1b). To explore this model further, we transferred naïve OT-I and OT-I/DNRII CD8 T cells (together or separately) into sub-lethally irradiated IL-15 deficient hosts. As we reported previously, lack of IL-15 in the lymphopenic host leads to reduced expansion of OT-I cells at late stages of the response [17] and this was observed for both WT and DNRII OT-I cells (Fig. 3 and S2). However, OT-I/DNRII T cells still exhibited an advantage compared to their WT counterparts in the IL-15-deficient hosts, as measured by both their proliferation (Fig. 3a) and accumulation (Fig. 3b). As was observed with B6 hosts, OT-I/DNRII had an even greater advantage in situations where OT-I and OT-I/DNRII cells were co-transferred into the same IL-15−/− recipients (Fig. 3b and S2). Together, these data indicate that the competitive advantage of the DNRII pool during HP is not solely due to improved IL-15 sensitivity (although IL-15 enhances the proliferative response of both WT and DNRII populations).

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