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Cell Rep. 2018 Apr 17;23(3):796-807. doi: 10.1016/j.celrep.2018.03.099.

KAP1 Regulates Regulatory T Cell Function and Proliferation in Both Foxp3-Dependent and -Independent Manners.

Author information

1
Immunology Program, Benaroya Research Institute, 1201 9th Avenue, Seattle, WA 98101-2795, USA.
2
Immunology 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, USA.
3
Department of Immunology, M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030, USA.
4
Immunology Program, Benaroya Research Institute, 1201 9th Avenue, Seattle, WA 98101-2795, USA; Department of Immunology, University of Washington School of Medicine, Seattle, WA, USA. Electronic address: sziegler@benaroyaresearch.org.

Abstract

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.

KEYWORDS:

Foxp3; KAP1; TIF1b; TRIM28; Treg; autoimmunity; regulatory T cells

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