KAP1 Regulates Regulatory T Cell Function and Proliferation in Both Foxp3-Dependent and -Independent Manners
Summary: Regulatory T cells (Tregs) are indispensable for the establishment of tolerance of self-antigens in animals. The transcriptional regulator Foxp3 is critical for Treg development and function, controlling the expression of genes important for Tregs through interactions with binding partners....
Main Authors: | , , , , , |
---|---|
Format: | Article |
Language: | English |
Published: |
Elsevier
2018-04-01
|
Series: | Cell Reports |
Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124718304753 |
id |
doaj-309b6192d7e94d4a9cf659f07064d9f0 |
---|---|
record_format |
Article |
spelling |
doaj-309b6192d7e94d4a9cf659f07064d9f02020-11-24T21:34:40ZengElsevierCell Reports2211-12472018-04-01233796807KAP1 Regulates Regulatory T Cell Function and Proliferation in Both Foxp3-Dependent and -Independent MannersShigeru Tanaka0Christian Pfleger1Jen-Feng Lai2Florence Roan3Shao-Cong Sun4Steven F. Ziegler5Immunology Program, Benaroya Research Institute, 1201 9th Avenue, Seattle, WA 98101-2795, USAImmunology Program, Benaroya Research Institute, 1201 9th Avenue, Seattle, WA 98101-2795, USAImmunology Program, Benaroya Research Institute, 1201 9th Avenue, Seattle, WA 98101-2795, USAImmunology Program, Benaroya Research Institute, 1201 9th Avenue, Seattle, WA 98101-2795, USA; Division of Allergy and Infectious Diseases, University of Washington School of Medicine, Seattle, WA, USADepartment of Immunology, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USAImmunology Program, Benaroya Research Institute, 1201 9th Avenue, Seattle, WA 98101-2795, USA; Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA; Corresponding authorSummary: Regulatory T cells (Tregs) are indispensable for the establishment of tolerance of self-antigens in animals. The transcriptional regulator Foxp3 is critical for Treg development and function, controlling the expression of genes important for Tregs through interactions with binding partners. We previously reported KAP1 as a binding partner of FOXP3 in human Tregs, but the mechanisms by which KAP1 affects Treg function were unclear. In this study, we analyzed mice with Treg-specific deletion of KAP1 and found that they develop spontaneous autoimmune disease. KAP1-deficient Tregs failed to induce Foxp3-regulated Treg signature genes. In addition, KAP1-deficient Tregs were less proliferative due to the decreased expression of Slc1a5, whose expression was KAP1 dependent but Foxp3 independent. This reduced expression of Slc1a5 resulted in reduced mTORC1 activation. Thus, our data suggest that KAP1 regulates Treg function in a Foxp3-dependent manner and also controls Treg proliferation in a Foxp3-independent manner. : Tanaka et al. demonstrate that KAP1 works together with Foxp3, the master transcription factor of regulatory T cells (Tregs), to induce effector molecules and Treg-specific KAP1-deficient mice develop autoimmunity. KAP1 also regulates cell proliferation independent from Foxp3 by inducing a glutamine transporter, Slc1a5. Keywords: regulatory T cells, Treg, Foxp3, KAP1, TRIM28, TIF1b, autoimmunityhttp://www.sciencedirect.com/science/article/pii/S2211124718304753 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Shigeru Tanaka Christian Pfleger Jen-Feng Lai Florence Roan Shao-Cong Sun Steven F. Ziegler |
spellingShingle |
Shigeru Tanaka Christian Pfleger Jen-Feng Lai Florence Roan Shao-Cong Sun Steven F. Ziegler KAP1 Regulates Regulatory T Cell Function and Proliferation in Both Foxp3-Dependent and -Independent Manners Cell Reports |
author_facet |
Shigeru Tanaka Christian Pfleger Jen-Feng Lai Florence Roan Shao-Cong Sun Steven F. Ziegler |
author_sort |
Shigeru Tanaka |
title |
KAP1 Regulates Regulatory T Cell Function and Proliferation in Both Foxp3-Dependent and -Independent Manners |
title_short |
KAP1 Regulates Regulatory T Cell Function and Proliferation in Both Foxp3-Dependent and -Independent Manners |
title_full |
KAP1 Regulates Regulatory T Cell Function and Proliferation in Both Foxp3-Dependent and -Independent Manners |
title_fullStr |
KAP1 Regulates Regulatory T Cell Function and Proliferation in Both Foxp3-Dependent and -Independent Manners |
title_full_unstemmed |
KAP1 Regulates Regulatory T Cell Function and Proliferation in Both Foxp3-Dependent and -Independent Manners |
title_sort |
kap1 regulates regulatory t cell function and proliferation in both foxp3-dependent and -independent manners |
publisher |
Elsevier |
series |
Cell Reports |
issn |
2211-1247 |
publishDate |
2018-04-01 |
description |
Summary: Regulatory T cells (Tregs) are indispensable for the establishment of tolerance of self-antigens in animals. The transcriptional regulator Foxp3 is critical for Treg development and function, controlling the expression of genes important for Tregs through interactions with binding partners. We previously reported KAP1 as a binding partner of FOXP3 in human Tregs, but the mechanisms by which KAP1 affects Treg function were unclear. In this study, we analyzed mice with Treg-specific deletion of KAP1 and found that they develop spontaneous autoimmune disease. KAP1-deficient Tregs failed to induce Foxp3-regulated Treg signature genes. In addition, KAP1-deficient Tregs were less proliferative due to the decreased expression of Slc1a5, whose expression was KAP1 dependent but Foxp3 independent. This reduced expression of Slc1a5 resulted in reduced mTORC1 activation. Thus, our data suggest that KAP1 regulates Treg function in a Foxp3-dependent manner and also controls Treg proliferation in a Foxp3-independent manner. : Tanaka et al. demonstrate that KAP1 works together with Foxp3, the master transcription factor of regulatory T cells (Tregs), to induce effector molecules and Treg-specific KAP1-deficient mice develop autoimmunity. KAP1 also regulates cell proliferation independent from Foxp3 by inducing a glutamine transporter, Slc1a5. Keywords: regulatory T cells, Treg, Foxp3, KAP1, TRIM28, TIF1b, autoimmunity |
url |
http://www.sciencedirect.com/science/article/pii/S2211124718304753 |
work_keys_str_mv |
AT shigerutanaka kap1regulatesregulatorytcellfunctionandproliferationinbothfoxp3dependentandindependentmanners AT christianpfleger kap1regulatesregulatorytcellfunctionandproliferationinbothfoxp3dependentandindependentmanners AT jenfenglai kap1regulatesregulatorytcellfunctionandproliferationinbothfoxp3dependentandindependentmanners AT florenceroan kap1regulatesregulatorytcellfunctionandproliferationinbothfoxp3dependentandindependentmanners AT shaocongsun kap1regulatesregulatorytcellfunctionandproliferationinbothfoxp3dependentandindependentmanners AT stevenfziegler kap1regulatesregulatorytcellfunctionandproliferationinbothfoxp3dependentandindependentmanners |
_version_ |
1725948278714925056 |