期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 202, 期 8, 页码 1099-1108出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20050003
关键词
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资金
- NCI NIH HHS [CA22556, R37 CA022556, R01 CA022556] Funding Source: Medline
- NIAID NIH HHS [R01 AI045809, AI41079, AI45809] Funding Source: Medline
- NIA NIH HHS [AG20186, R01 AG020186] Funding Source: Medline
Mice that are deficient in suppressor of cytokine signaling-1 (SOCS-1) succumb to neonatal mortality that is associated with extensive cellular infiltration of many tissues. T cells seem to be necessary for disease, which can be alleviated largely by neutralizing interferon-gamma. Examining T cell receptor (TCR) specificity shows that even monospecific T cells can mediate disease in SOCS-1-deficient mice, although disease onset is substantially faster with a polyclonal T cell repertoire. A major phenotype of SOCS-1(-/-) mice is the accumulation of CD44(high)CD8(+) peripheral T cells. We show that SOCS-1-deficient CD8, but not CD4, T cells proliferate when transferred into normal (T cell-sufficient) mice, and that this is dependent on two signals: interleukin (IL)-15 and self-ligands that are usually only capable of stimulating homeostatic expansion in T cell-deficient mice. Our findings reveal that SOCS-1 normally down-regulates the capacity of IL-15 to drive activation and proliferation of naive CD8 T cells receiving TCR survival signals from self-ligands. We show that such dysregulated proliferation impairs the deletion of a highly autoreactive subset of CD8 T cells, and increases their potential for autoimmunity. Therefore, impaired deletion of highly autoreactive CD8 T cells, together with uncontrolled activation of naive CD8 T cells by homeostatic survival ligands, may provide a basis for the T cell-mediated disease of SOCS-1(-/-) mice.
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