Journal
JOURNAL OF IMMUNOLOGY
Volume 170, Issue 8, Pages 4127-4133Publisher
AMER ASSOC IMMUNOLOGISTS
DOI: 10.4049/jimmunol.170.8.4127
Keywords
-
Categories
Funding
- NIAID NIH HHS [R01 AI060921, AI-37691, AI-43620, AI054643, AI-41521, AI-39678] Funding Source: Medline
- NICHD NIH HHS [HD-01056] Funding Source: Medline
- NIDDK NIH HHS [DK02771] Funding Source: Medline
Ask authors/readers for more resources
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)gamma-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 PLCgamma-1 activity. Finally, analogs that mimic the actions of diacylglycerol and inositol 1,4,5-triphosphate, the immediate products of PLCgamma-1 activity, restored integrin. avidity modulation and IL-2 production by anergic T cells. Thus, deficient coupling of PLCgamma-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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available