SOCS-1 regulates IL-15-driven homeostatic proliferation of antigen-naive CD8 T cells, limiting their autoimmune potential
- Davey, GM; Starr, R; Cornish, AL; Burghardt, JT; Alexander, WS; Carbone, FR; Surh, CD; Heath, WR;
Publication Year 2005-10-17, Volume 202, Issue #8, Page 1099-1108
- Journal Title
- JOURNAL OF EXPERIMENTAL MEDICINE
- Publication Type
- Journal Article
- 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.
- ROCKEFELLER UNIV PRESS
- RESTRICTED CROSS-PRESENTATION; CYTOKINE SIGNALING-1; POSITIVE SELECTION; IN-VIVO; INTERFERON-GAMMA; VIRUS-INFECTION; SELF-TOLERANCE; DENDRITIC CELL; MUTANT MICE; BOX MOTIF
- Publisher's Version
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- Refer to copyright notice on published article.
Creation Date: 2005-10-17 12:00:00Last Modified: 0001-01-01 12:00:00