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TRAF6 is a T cell–intrinsic negative regulator required for the maintenance of immune homeostasis

Nature Medicine volume 12, pages 1088–1092 (2006)Cite this article

Abstract

TRAF6 has a key role in the regulation of innate immune responses by mediating signals from both TNF receptor and interleukin-1 receptor/Toll-like receptor superfamilies. Here we show that T cell–specific deletion of TRAF6 unexpectedly results in multiorgan inflammatory disease. TRAF6-deficient T cells exhibit hyperactivation of the phosphatidylinositol 3-kinase (PI3K)-Akt pathway compared with wild-type T cells and, as a result, become resistant to suppression by CD4+CD25+ regulatory T cells. These data identify a previously unrecognized role for TRAF6 in the maintenance of peripheral tolerance, and suggest the presence of a T cell–intrinsic control mechanism to render responder T cells susceptible to tolerizing signals.

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Figure 1: Traf6-ΔT mice develop systemic inflammatory disease.
Figure 2: Defective CD4+CD25+ T cell–mediated suppression of Traf6-ΔT T-cell responders.
Figure 3: Traf6-ΔT CD4+ T cells exhibit normal upregulation of Il2 and IL-2 receptors, but hyperproliferate in the absence of CD28 costimulation.
Figure 4: TRAF6 negatively regulates PI3K-Akt activation.

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Acknowledgements

We thank the University of Pennsylvania Cancer Center Flow Cytometry Core for assistance with FACS; and A. Kuan, M. Walsh and E. Wilson for critical suggestions and technical assistance. This work is supported in part by grants from US National Institutes of Health (to Y.C., L.T.)

Author information

Author notes

  1. Takashi Kobayashi

    Present address: Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi Higashi-ku, Fukuoka, 812-8582, Japan

  2. Kwiyeom Yoon

    Present address: Division of Molecular Life Sciences and Center for Cell Signaling Research, Ewha Womans University, Seoul, 120-750, Republic of Korea

  3. Elise Chiffoleau

    Present address: INSERM Unité 437 and Institut de Transplantation et de Recherche en Transplantation, Nantes, F-44035, France

Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, 421 Curie Boulevard, Philadelphia, 19104, Pennsylvania, USA

    Carolyn G King, Takashi Kobayashi, Pedro J Cejas, Taesoo Kim, Kwiyeom Yoon, Gregory K Kim & Yongwon Choi

  2. Department of Medicine, University of Pennsylvania School of Medicine, 421 Curie Boulevard, Philadelphia, 19104, Pennsylvania, USA

    Elise Chiffoleau, Somia P Hickman, Patrick T Walsh & Laurence A Turka

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Correspondence to Yongwon Choi.

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Supplementary information

Supplementary Fig. 1

Generation of TRAF-ΔT mice using CD4-Cre mice. (PDF 1070 kb)

Supplementary Fig. 2

Immune cell infiltration in TRAF6-ΔT mice. (PDF 253 kb)

Supplementary Fig. 3

Phenotypic analysis of 10-week-old mice created by crossing floxed TRAF6 mice with Lck-Cre transgenic mice. (PDF 1991 kb)

Supplementary Fig. 4

TRAF6-ΔT mice do not exhibit any obvious abnormalities in central tolerance. (PDF 1286 kb)

Supplementary Fig. 5

Lymphoproliferative inflammatory disease in mixed chimera mice generated by reconstituting irradiated mice (CD45.1) with T cell—depleted bone marrow from both control (CD45.1) and TRAF6-ΔT mice, at 1:1 ratio. (PDF 1856 kb)

Supplementary Fig. 6

TRAF6-ΔT CD4+ T cells exhibit normal TCRβ downregulation. (PDF 491 kb)

Supplementary Fig. 7

TRAF6 negatively regulates PI3K-Akt activation. (PDF 613 kb)

Supplementary Fig. 8

TRAF6-ΔT CD4+ T cells exhibit normal susceptibility to Fas-mediated apoptosis. (PDF 310 kb)

Supplementary Methods (PDF 32 kb)

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King, C., Kobayashi, T., Cejas, P. et al. TRAF6 is a T cell–intrinsic negative regulator required for the maintenance of immune homeostasis. Nat Med 12, 1088–1092 (2006). https://doi.org/10.1038/nm1449

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