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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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.)
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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)
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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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DOI: https://doi.org/10.1038/nm1449
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