Cutting edge: requirement for TRAF6 in the induction of T cell anergy.
TRAF6, TNFR-associated factor 6, is a key adaptor downstream from the TNF receptor and TLR superfamily members. T cell-specific deletion of TRAF6 (TRAF6-DeltaT) was recently shown to result in the development of multiorgan inflammatory disease and the resistance of responder T cells to suppression by CD4+CD25+ regulatory T cells. In this study we examined the role of TRAF6 in an additional mechanism of peripheral tolerance, anergy. We have determined that the loss of TRAF6 restores the ability of CD28-/- T cells to proliferate and produce IL-2. Consistent with this, TRAF6-DeltaT T cells were resistant to anergizing signals both in vitro and in vivo. Resistance to anergy was correlated with decreased expression of Cbl-b. These findings reveal that in addition to its role in rendering T cells susceptible to control by CD4+CD25+ regulatory T cells, TRAF6 is essential for the induction of T cell anergy, implicating TRAF6 as a critical mediator of peripheral tolerance.
King
Carolyn G
CG
Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Buckler
Jodi L
JL
Kobayashi
Takashi
T
Hannah
Jeffrey R
JR
Bassett
Garrett
G
Kim
Taesoo
T
Pearce
Erika L
EL
Kim
Gregory G
GG
Turka
Laurence A
LA
Choi
Yongwon
Y
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000818:Animals; D015704:CD4 Antigens / Q000032:analysis; D017635:Clonal Anergy / Q000235:genetics*; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D051379:Mice; D018345:Mice, Knockout; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D015704:CD4 Antigens; C118387:Cblb protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D048029:TNF Receptor-Associated Factor 6; D050721:Proto-Oncogene Proteins c-cbl