Transient gain of effector function by CD8+ T cells undergoing peripheral tolerance to high-dose self-antigen.
Induction of peripheral T cell tolerance is mediated by bone marrow-derived dendritic cells that cross-present self-antigen to self-reactive T cells. The current model for peripheral CD8(+) T cell tolerance is that TCR engagement by self-antigen in the absence of costimulation results in abortive activation without development of effector function. Here we demonstrate in vivo that high-dose self-antigen ("signal 1") can compensate for lack of costimulation ("signal 2"), leading to full activation of and development of effector function by self-reactive T cells. In the setting of low-dose self-antigen, acquisition of effector function by self-reactive T cells is dependent on costimulation via CD40 ligation in vivo. However, gain of effector function in either setting does not prevent eventual tolerance of self-reactive CD8(+) T cells. These results suggest that the mechanisms for peripheral CD8(+) T cell tolerance are more complex than the proposed "signal 1 in the absence of signal 2" hypothesis. Further exploration of these mechanisms will have direct impact on the design of effective immunotherapy for autoimmune diseases, chronic infections and cancers.
Huang
Xiaopei
X
Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA.
Yang
Yiping
Y
D000818:Animals; D001324:Autoantigens / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D011014:Pneumonia / Q000276:immunology
D001324:Autoantigens; D019013:CD40 Antigens