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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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Extended expansion of OT-I/DNRII CD8 T cells as lymphopenic space becomes limiting.CFSE labeled CD44lo OT-I and OT-I/DNRII CD8 T cells were adoptively co-transferred into indicated B6 hosts. Host animals were sacrificed at the indicated timepoints for analysis of donor and host cells. (A, B) OT-I and OT-I/DNRII CD8 T cells were cotransfered into irradiated hosts and analyzed 2, 3 and 4 weeks later. (n = 3 per group) (A) CFSE dye dilution is shown for OT-I cells (left panel), and OT-I/DNRII cells (right panel) CD8 T cells. differentiated by congenic markers. (B) OT-I and OT-I/DNRII CD8 T cell recovery in the lymph node and spleen over time (n = 3 per group). Results are expressed as mean ± SD. (C) CFSE dilution of OT-I and OT-I/DNRII CD8 T cells three weeks after co-transfer into unirradiated (lymphoreplete) B6 hosts. Kb-OVA tetramer pulldowns were used to enrich for OT-I and OT-I/DNRII CD8 T cells. All data are representative of at least 3 independent experiments.
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pone-0042268-g002: Extended expansion of OT-I/DNRII CD8 T cells as lymphopenic space becomes limiting.CFSE labeled CD44lo OT-I and OT-I/DNRII CD8 T cells were adoptively co-transferred into indicated B6 hosts. Host animals were sacrificed at the indicated timepoints for analysis of donor and host cells. (A, B) OT-I and OT-I/DNRII CD8 T cells were cotransfered into irradiated hosts and analyzed 2, 3 and 4 weeks later. (n = 3 per group) (A) CFSE dye dilution is shown for OT-I cells (left panel), and OT-I/DNRII cells (right panel) CD8 T cells. differentiated by congenic markers. (B) OT-I and OT-I/DNRII CD8 T cell recovery in the lymph node and spleen over time (n = 3 per group). Results are expressed as mean ± SD. (C) CFSE dilution of OT-I and OT-I/DNRII CD8 T cells three weeks after co-transfer into unirradiated (lymphoreplete) B6 hosts. Kb-OVA tetramer pulldowns were used to enrich for OT-I and OT-I/DNRII CD8 T cells. All data are representative of at least 3 independent experiments.

Mentions: It was possible that the OT-I/DNRII population produced factors that enhanced HP of all T cells in the lymphopenic environment and/or which delayed repopulation of the host lymphoid compartment following sublethal irradiation (allowing for extended homeostatic proliferation of donor T cells). To test whether such non-autonomous effects occurred in our system, we studied the proliferation and expansion of co-transferred OT-I and OT-I/DNRII in lymphopenic hosts. Interestingly, the enhanced proliferation of OT-I/DNRII cells was further exaggerated in the co-transfer setting (Fig. 1d and S2), suggesting a competitive advantage of the DNRII pool over the WT OT-I population, and arguing against an environmental effect induced by the DNRII cells. We also used this approach to investigate the termination of HP in the lymphopenic hosts. Naïve OT-I and OT-I/DNRII cells were analyzed at 2, 3 and 4 weeks after co-transfer into sub-lethally irradiated B6 hosts (Fig. 2a and b). As expected from previous studies [17], OT-I T cell proliferation in irradiated hosts halts between week 2 and 3 post-transfer, as evidenced by lack of substantial additional proliferation or accumulation (Fig. 2a and b). In stark contrast, the OT-I/DNRII pool continues proliferating and accumulating up to week 4 post-transfer (Fig. 2a and b). This continued expansion of OT-I/DNRII T cells was evident despite the reconstitution of the host CD8 T cell pool over the same time course (Fig. S3), indicating the DNRII population has impaired sensitivity to the size of the T cell compartment. Furthermore, the size of the OT-I/DNRII pool was still elevated 3 months after adoptive transfer (Fig. S4), implying that these cells were maintained long after the host T cell pool had been restored. Together, these data suggest that TGF-β signaling sensitivity does not influence initial stages of lymphopenia-induced HP, but has an autonomous role in restraining T cell homeostasis as the T cell compartment fills.


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)

Extended expansion of OT-I/DNRII CD8 T cells as lymphopenic space becomes limiting.CFSE labeled CD44lo OT-I and OT-I/DNRII CD8 T cells were adoptively co-transferred into indicated B6 hosts. Host animals were sacrificed at the indicated timepoints for analysis of donor and host cells. (A, B) OT-I and OT-I/DNRII CD8 T cells were cotransfered into irradiated hosts and analyzed 2, 3 and 4 weeks later. (n = 3 per group) (A) CFSE dye dilution is shown for OT-I cells (left panel), and OT-I/DNRII cells (right panel) CD8 T cells. differentiated by congenic markers. (B) OT-I and OT-I/DNRII CD8 T cell recovery in the lymph node and spleen over time (n = 3 per group). Results are expressed as mean ± SD. (C) CFSE dilution of OT-I and OT-I/DNRII CD8 T cells three weeks after co-transfer into unirradiated (lymphoreplete) B6 hosts. Kb-OVA tetramer pulldowns were used to enrich for OT-I and OT-I/DNRII CD8 T cells. All data are representative of at least 3 independent experiments.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3412850&req=5

pone-0042268-g002: Extended expansion of OT-I/DNRII CD8 T cells as lymphopenic space becomes limiting.CFSE labeled CD44lo OT-I and OT-I/DNRII CD8 T cells were adoptively co-transferred into indicated B6 hosts. Host animals were sacrificed at the indicated timepoints for analysis of donor and host cells. (A, B) OT-I and OT-I/DNRII CD8 T cells were cotransfered into irradiated hosts and analyzed 2, 3 and 4 weeks later. (n = 3 per group) (A) CFSE dye dilution is shown for OT-I cells (left panel), and OT-I/DNRII cells (right panel) CD8 T cells. differentiated by congenic markers. (B) OT-I and OT-I/DNRII CD8 T cell recovery in the lymph node and spleen over time (n = 3 per group). Results are expressed as mean ± SD. (C) CFSE dilution of OT-I and OT-I/DNRII CD8 T cells three weeks after co-transfer into unirradiated (lymphoreplete) B6 hosts. Kb-OVA tetramer pulldowns were used to enrich for OT-I and OT-I/DNRII CD8 T cells. All data are representative of at least 3 independent experiments.
Mentions: It was possible that the OT-I/DNRII population produced factors that enhanced HP of all T cells in the lymphopenic environment and/or which delayed repopulation of the host lymphoid compartment following sublethal irradiation (allowing for extended homeostatic proliferation of donor T cells). To test whether such non-autonomous effects occurred in our system, we studied the proliferation and expansion of co-transferred OT-I and OT-I/DNRII in lymphopenic hosts. Interestingly, the enhanced proliferation of OT-I/DNRII cells was further exaggerated in the co-transfer setting (Fig. 1d and S2), suggesting a competitive advantage of the DNRII pool over the WT OT-I population, and arguing against an environmental effect induced by the DNRII cells. We also used this approach to investigate the termination of HP in the lymphopenic hosts. Naïve OT-I and OT-I/DNRII cells were analyzed at 2, 3 and 4 weeks after co-transfer into sub-lethally irradiated B6 hosts (Fig. 2a and b). As expected from previous studies [17], OT-I T cell proliferation in irradiated hosts halts between week 2 and 3 post-transfer, as evidenced by lack of substantial additional proliferation or accumulation (Fig. 2a and b). In stark contrast, the OT-I/DNRII pool continues proliferating and accumulating up to week 4 post-transfer (Fig. 2a and b). This continued expansion of OT-I/DNRII T cells was evident despite the reconstitution of the host CD8 T cell pool over the same time course (Fig. S3), indicating the DNRII population has impaired sensitivity to the size of the T cell compartment. Furthermore, the size of the OT-I/DNRII pool was still elevated 3 months after adoptive transfer (Fig. S4), implying that these cells were maintained long after the host T cell pool had been restored. Together, these data suggest that TGF-β signaling sensitivity does not influence initial stages of lymphopenia-induced HP, but has an autonomous role in restraining T cell homeostasis as the T cell compartment fills.

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