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-1-Dependent Integrin Avidity Modulation1
* Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; and
Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, PA 19104
Ag receptor engagement without costimulation induces a tolerant state in CD4+ T cells termed anergy. Anergic CD4+ T cells are primarily characterized by the inability to produce IL-2, but the biochemical basis for this functional defect is not completely understood. We demonstrate that primary CD4+ T cells anergized by costimulatory blockade exhibit impaired TCR-coupled phospholipase C (PLC)
-1 activation. This defect is associated with the marked reduction of multiple downstream signaling events required for IL-2 transcription, including mobilization of intracellular Ca2+ and activation of the mitogen-activated protein kinase cascade. We also found that primary anergic CD4+ T cells fail entirely to modulate their integrin binding avidity in response to TCR stimulation. Integrin avidity modulation is required for full T cell activation and effector function, and as we show in this study, is completely dependent upon PLC-1 activity. Finally, analogs that mimic the actions of diacylglycerol and inositol 1,4,5-triphosphate, the immediate products of PLC-1 activity, restored integrin avidity modulation and IL-2 production by anergic T cells. Thus, deficient coupling of PLC-1 to the TCR appears to be a central biochemical defect that could potentially account for the failure of multiple functional responses in primary anergic CD4+ T cells.
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