期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 209, 期 10, 页码 1781-1795出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20120058
关键词
-
资金
- intramural program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health
Negative selection and regulatory T (T reg) cell development are two thymus-dependent processes necessary for the enforcement of self-tolerance, and both require high-affinity interactions between the T cell receptor (TCR) and self-ligands. However, it remains unclear if they are similarly impacted by alterations in TCR signaling potential. We generated a knock-in allele (6F) of the TCR zeta chain gene encoding a mutant protein lacking signaling capability whose expression is controlled by endogenous zeta regulatory sequences. Although negative selection was defective in 6F/6F mice, leading to the survival of autoreactive T cells, 6F/6F mice did not develop autoimmune disease. We found that 6F/6F mice generated increased numbers of thymus-derived T reg cells. We show that attenuation of TCR signaling potential selectively impacts downstream signaling responses and that this differential effect favors Foxp3 expression and T reg cell lineage commitment. These results identify a potential compensatory pathway for the enforcement of immune tolerance in response to defective negative selection caused by reduced TCR signaling capability.
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