Artikel
TGFb bound to GARP promotes acetylation-mediated FOXP3 protein stabilization
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Autoren
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Peter Lehmkuhl
- Sektion Rheumatologie und Klinische Immunologie, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, München
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Benedikt Zapp
- Sektion Rheumatologie und Klinische Immunologie, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, München
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Hendrik Schulze-Koops
- Sektion Rheumatologie und Klinische Immunologie, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, München
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Alla Skapenko
- Sektion Rheumatologie und Klinische Immunologie, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München, München
| Veröffentlicht: | 5. Februar 2019 |
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Gliederung
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Background: Regulatory T cells (Tregs) play a critical role in maintaining homeostasis and limiting autoimmunity. The transcription factor Forkhead box P3 (FOXP3) has been identified as the key regulator of Treg function and development. Its activity and stability are tightly regulated by acetylation dependent on the interplay between histone deacetylases (HDAC) and histone acetyltransferases (HAT). Tregs express distinctively on their cell surface glycoprotein A repetitions predominant (GARP). GARP binds latent TGFb and provides to Tregs an available pool of TGFb. The function of this TGFb source for Tregs has not been investigated yet. Treg-derived TGFb might on the one hand be involved in mediating suppressive functions of Tregs and on the other hand be important for maintaining Treg homeostasis. The function of surface TGFb bound to GARP was analyzed utilizing GARP-deficient Tregs from conditional CD4 specific GARP knockout mice.
Methods: CD4 positive Tregs were stimulated and analyzed for mRNA expression by real time PCR and for protein acetylation and phosphorylation by intracellular flow cytometry.
Results: GARP-deficient Tregs exhibited a markedly diminished intracellular protein acetylation. Acetylation of FOXP3 was also significantly lower. Consistently, expression of a Treg specific HDAC, HDAC9, was up regulated in Tregs lacking GARP. Total protein acetylation, acetylation of FOXP3 and HDAC9 expression levels could be restored by addition of exogenous TGFb. In this regard basal phosphorylation of TGFb-dependent transcription factors SMAD2/3 was diminished in Tregs lacking GARP. Further analysis revealed an unstable phenotype of GARP-deficient Tregs characterized by a shorter half-life of FOXP3, a faster loss of FOXP3 in response to anti-CD3/28 stimulation and restricted regulatory capacity.
Conclusion: Lack of GARP on the cell surface results in a reduced TGFb availability and in a decreased TGFb signaling in CD4 Tregs. Diminished TGFb signaling leads in turn to an elevated HDAC9 expression and to a decreased FOXP3 acetylation. Lower acetylated FOXP3 determines an instable phenotype of GARP-deficient Tregs and their failure to proper regulate an immune reaction.
