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-Independent Actions in T Cell Homeostasis1
* The Walter and Eliza Hall Institute of Medical Research and
Cooperative Research Center for Cellular Growth Factors, Parkville, Victoria, Australia; and
Department of Pathology and Immunology, Central and Eastern Clinical School, Monash University, Prahran, Victoria, Australia
Suppressor of cytokine signaling (SOCS)-1 is a member of a family
of proteins that negatively regulate cytokine signaling pathways. We
have previously established that SOCS-1 is a key regulator of IFN-
signaling and that IFN- is responsible for the complex inflammatory
disease that leads to the death of SOCS-1-deficient
mice. In this study, we provide evidence that SOCS-1 is also a critical
regulator of IFN--independent immunoregulatory factors. Mice lacking
both SOCS-1 and IFN-, although
outwardly healthy, have clear abnormalities in their immune system,
including a reduced ratio of CD4:CD8 T cells in lymphoid tissues and
increased expression of T cell activation markers. To examine the
contribution of TCR Ag specificity to these immune defects, we have
generated two lines of SOCS-1-deficient mice expressing
a transgenic TCR specific for an exogenous Ag, OVA (OT-I
and OT-II). Although TCR transgenic
SOCS-1-/- mice have a longer
lifespan than nontransgenic
SOCS-1-/- mice, they still die as
young adults with inflammatory disease and the TCR transgenic
SOCS-1-/- T cells appear activated
despite the absence of OVA. This suggests that both Ag-dependent and
-independent mechanisms contribute to the disease in
SOCS-1-deficient mice. Thus, SOCS-1 is a critical
regulator of T cell activation and homeostasis, and its influence
extends beyond regulating IFN- signaling.
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