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Transforming growth factor-beta suppresses the activation of CD8+ T-cells when naive but promotes their survival and function once antigen experienced: a two-faced impact on autoimmunity.

Filippi CM, Juedes AE, Oldham JE, Ling E, Togher L, Peng Y, Flavell RA, von Herrath MG - Diabetes (2008)

Bottom Line: These results pointed to drastically opposite roles of TGF-beta on naïve compared with antigen-experienced/memory CD8(+) T-cells.The effect of TGF-beta on CD8(+) T-cells is dependent on their differentiation status and activation history.These results highlight a novel aspect of the pleiotropic nature of TGF-beta and have implications for the design of immune therapies involving this cytokine.

View Article: PubMed Central - PubMed

Affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.

ABSTRACT

Objective: Transforming growth factor-beta (TGF-beta) can exhibit strong immune suppression but has also been shown to promote T-cell growth. We investigated the differential effect of this cytokine on CD8(+) T-cells in autoimmunity and antiviral immunity.

Research design and methods: We used mouse models for virally induced type 1 diabetes in conjunction with transgenic systems enabling manipulation of TGF-beta expression or signaling in vivo.

Results: Surprisingly, when expressed selectively in the pancreas, TGF-beta reduced apoptosis of differentiated autoreactive CD8(+) T-cells, favoring their expansion and infiltration of the islets. These results pointed to drastically opposite roles of TGF-beta on naïve compared with antigen-experienced/memory CD8(+) T-cells. Indeed, in the absence of functional TGF-beta signaling in T-cells, fast-onset type 1 diabetes caused by activation of naïve CD8(+) T-cells occurred faster, whereas slow-onset disease depending on accumulation and activation of antigen-experienced/memory CD8(+) T-cells was decreased. TGF-beta receptor-deficient CD8(+) T-cells showed enhanced activation and expansion after lymphocytic choriomeningitis virus infection in vivo but were more prone to apoptosis once antigen experienced and failed to survive as functional memory cells. In vitro, TGF-beta suppressed naïve CD8(+) T-cell activation and gamma-interferon production, whereas memory CD8(+) T-cells stimulated in the presence of TGF-beta showed enhanced survival and increased production of interleukin-17 in conjunction with gamma-interferon.

Conclusions: The effect of TGF-beta on CD8(+) T-cells is dependent on their differentiation status and activation history. These results highlight a novel aspect of the pleiotropic nature of TGF-beta and have implications for the design of immune therapies involving this cytokine.

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Related in: MedlinePlus

Absence of TGF-β receptor signaling in T-cells has opposite effects on virally induced autoimmune diabetes depending on the effector mechanism. dnTGFβR mice were crossed onto fast-onset diabetes RIP-GP or slow-onset diabetes RIP-NP lines. Groups of RIP-GP.dnTGFβR (A) mice, RIP-NP.dnTGFβR (B) mice, and their single transgenic RIP-GP or RIP-NP littermates were infected with LCMV, and diabetes incidence was monitored by measuring blood glucose. Mice were considered diabetic when blood glucose exceeded 300 mg/dl.
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f3: Absence of TGF-β receptor signaling in T-cells has opposite effects on virally induced autoimmune diabetes depending on the effector mechanism. dnTGFβR mice were crossed onto fast-onset diabetes RIP-GP or slow-onset diabetes RIP-NP lines. Groups of RIP-GP.dnTGFβR (A) mice, RIP-NP.dnTGFβR (B) mice, and their single transgenic RIP-GP or RIP-NP littermates were infected with LCMV, and diabetes incidence was monitored by measuring blood glucose. Mice were considered diabetic when blood glucose exceeded 300 mg/dl.

Mentions: These observations pointed to opposite roles of TGF-β on naïve compared with antigen-experienced/memory CD8+ T-cells. We thus evaluated the impact of TGF-β in two type 1 diabetes models that differed in terms of requirement for CD8+ T-cell activation: the fast-onset C57BL/6 RIP-GP model, which is caused by robust activation of naïve CD8+ T-cells, and the slow-onset C57BL/6 RIP-NP model, which results from accumulation and activation of antigen-experienced/memory CD8+ T-cells. We generated C57BL/6 RIP-GP and C57BL/6 RIP-NP mice in which autoreactive CD8+ T-cells are unable to signal through the TGF-β receptor by crossing these mice with dnTGFβR mice, which express a dominant-negative TGF-β receptor specifically in T-cells. Although “naïve-dependent” fast-onset diabetes was dramatically accelerated in RIP-GP.dnTGFβR compared with RIP-GP mice (Fig. 3A), incidence of “memory-dependent” slow-onset diabetes was reduced more than twofold in RIP-NP.dnTGFβR compared with RIP-NP mice (Fig. 3B). Absence of TGF-β receptor signaling in T-cells resulted in a threefold increase in the total number of LCMV-specific CD8+ T-cells in the spleen 7 days after LCMV infection (Fig. 4A). Thus, impaired responsiveness of naïve CD8+ T-cells to TGF-β enhanced their activation and expansion, which likely accounted for accelerated diabetes in the RIP-GP.dnTGFβR group and in the few RIP-NP.dnTGFβR mice that developed disease (between 1 and 2 weeks after infection in this otherwise slow-onset model). However, by day 30 the overall number of GP33-specific CD8+ T-cells was similar in wild-type and dnTGFβR mice (Fig. 4B), indicating that TGF-β–nonresponsive CD8+ T-cells had undergone increased contraction. Furthermore, TGF-β receptor–deficient memory CD8+ T-cells were more prone to apoptosis (Fig. 4C) and completely defective in terms of secondary expansion (Fig. 4D) when stimulated by LCMV-infected antigen-presenting cells in vitro. Thus, impaired responsiveness of activated CD8+ T-cells to TGF-β diminished their survival and maintenance as memory cells, which likely accounted for reduced slow-onset diabetes in the RIP-NP.dnTGFβR system. This indicates that TGF-β prevents activation of naïve CD8+ T-cells, which cause fast-onset diabetes, but promotes the survival and accumulation of antigen-experienced cells, which cause slow-onset disease.


Transforming growth factor-beta suppresses the activation of CD8+ T-cells when naive but promotes their survival and function once antigen experienced: a two-faced impact on autoimmunity.

Filippi CM, Juedes AE, Oldham JE, Ling E, Togher L, Peng Y, Flavell RA, von Herrath MG - Diabetes (2008)

Absence of TGF-β receptor signaling in T-cells has opposite effects on virally induced autoimmune diabetes depending on the effector mechanism. dnTGFβR mice were crossed onto fast-onset diabetes RIP-GP or slow-onset diabetes RIP-NP lines. Groups of RIP-GP.dnTGFβR (A) mice, RIP-NP.dnTGFβR (B) mice, and their single transgenic RIP-GP or RIP-NP littermates were infected with LCMV, and diabetes incidence was monitored by measuring blood glucose. Mice were considered diabetic when blood glucose exceeded 300 mg/dl.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2551678&req=5

f3: Absence of TGF-β receptor signaling in T-cells has opposite effects on virally induced autoimmune diabetes depending on the effector mechanism. dnTGFβR mice were crossed onto fast-onset diabetes RIP-GP or slow-onset diabetes RIP-NP lines. Groups of RIP-GP.dnTGFβR (A) mice, RIP-NP.dnTGFβR (B) mice, and their single transgenic RIP-GP or RIP-NP littermates were infected with LCMV, and diabetes incidence was monitored by measuring blood glucose. Mice were considered diabetic when blood glucose exceeded 300 mg/dl.
Mentions: These observations pointed to opposite roles of TGF-β on naïve compared with antigen-experienced/memory CD8+ T-cells. We thus evaluated the impact of TGF-β in two type 1 diabetes models that differed in terms of requirement for CD8+ T-cell activation: the fast-onset C57BL/6 RIP-GP model, which is caused by robust activation of naïve CD8+ T-cells, and the slow-onset C57BL/6 RIP-NP model, which results from accumulation and activation of antigen-experienced/memory CD8+ T-cells. We generated C57BL/6 RIP-GP and C57BL/6 RIP-NP mice in which autoreactive CD8+ T-cells are unable to signal through the TGF-β receptor by crossing these mice with dnTGFβR mice, which express a dominant-negative TGF-β receptor specifically in T-cells. Although “naïve-dependent” fast-onset diabetes was dramatically accelerated in RIP-GP.dnTGFβR compared with RIP-GP mice (Fig. 3A), incidence of “memory-dependent” slow-onset diabetes was reduced more than twofold in RIP-NP.dnTGFβR compared with RIP-NP mice (Fig. 3B). Absence of TGF-β receptor signaling in T-cells resulted in a threefold increase in the total number of LCMV-specific CD8+ T-cells in the spleen 7 days after LCMV infection (Fig. 4A). Thus, impaired responsiveness of naïve CD8+ T-cells to TGF-β enhanced their activation and expansion, which likely accounted for accelerated diabetes in the RIP-GP.dnTGFβR group and in the few RIP-NP.dnTGFβR mice that developed disease (between 1 and 2 weeks after infection in this otherwise slow-onset model). However, by day 30 the overall number of GP33-specific CD8+ T-cells was similar in wild-type and dnTGFβR mice (Fig. 4B), indicating that TGF-β–nonresponsive CD8+ T-cells had undergone increased contraction. Furthermore, TGF-β receptor–deficient memory CD8+ T-cells were more prone to apoptosis (Fig. 4C) and completely defective in terms of secondary expansion (Fig. 4D) when stimulated by LCMV-infected antigen-presenting cells in vitro. Thus, impaired responsiveness of activated CD8+ T-cells to TGF-β diminished their survival and maintenance as memory cells, which likely accounted for reduced slow-onset diabetes in the RIP-NP.dnTGFβR system. This indicates that TGF-β prevents activation of naïve CD8+ T-cells, which cause fast-onset diabetes, but promotes the survival and accumulation of antigen-experienced cells, which cause slow-onset disease.

Bottom Line: These results pointed to drastically opposite roles of TGF-beta on naïve compared with antigen-experienced/memory CD8(+) T-cells.The effect of TGF-beta on CD8(+) T-cells is dependent on their differentiation status and activation history.These results highlight a novel aspect of the pleiotropic nature of TGF-beta and have implications for the design of immune therapies involving this cytokine.

View Article: PubMed Central - PubMed

Affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.

ABSTRACT

Objective: Transforming growth factor-beta (TGF-beta) can exhibit strong immune suppression but has also been shown to promote T-cell growth. We investigated the differential effect of this cytokine on CD8(+) T-cells in autoimmunity and antiviral immunity.

Research design and methods: We used mouse models for virally induced type 1 diabetes in conjunction with transgenic systems enabling manipulation of TGF-beta expression or signaling in vivo.

Results: Surprisingly, when expressed selectively in the pancreas, TGF-beta reduced apoptosis of differentiated autoreactive CD8(+) T-cells, favoring their expansion and infiltration of the islets. These results pointed to drastically opposite roles of TGF-beta on naïve compared with antigen-experienced/memory CD8(+) T-cells. Indeed, in the absence of functional TGF-beta signaling in T-cells, fast-onset type 1 diabetes caused by activation of naïve CD8(+) T-cells occurred faster, whereas slow-onset disease depending on accumulation and activation of antigen-experienced/memory CD8(+) T-cells was decreased. TGF-beta receptor-deficient CD8(+) T-cells showed enhanced activation and expansion after lymphocytic choriomeningitis virus infection in vivo but were more prone to apoptosis once antigen experienced and failed to survive as functional memory cells. In vitro, TGF-beta suppressed naïve CD8(+) T-cell activation and gamma-interferon production, whereas memory CD8(+) T-cells stimulated in the presence of TGF-beta showed enhanced survival and increased production of interleukin-17 in conjunction with gamma-interferon.

Conclusions: The effect of TGF-beta on CD8(+) T-cells is dependent on their differentiation status and activation history. These results highlight a novel aspect of the pleiotropic nature of TGF-beta and have implications for the design of immune therapies involving this cytokine.

Show MeSH
Related in: MedlinePlus