[HTML][HTML] CTLA-4 activation of phosphatidylinositol 3-kinase (PI 3-K) and protein kinase B (PKB/AKT) sustains T-cell anergy without cell death

H Schneider, E Valk, R Leung, CE Rudd - PloS one, 2008 - journals.plos.org
H Schneider, E Valk, R Leung, CE Rudd
PloS one, 2008journals.plos.org
The balance of T-cell proliferation, anergy and apoptosis is central to immune function. In
this regard, co-receptor CTLA-4 is needed for the induction of anergy and tolerance. One
central question concerns the mechanism by which CTLA-4 can induce T-cell non-
responsiveness without a concurrent induction of antigen induced cell death (AICD). In this
study, we show that CTLA-4 activation of the phosphatidylinositol 3-kinase (PI 3-K) and
protein kinase B (PKB/AKT) sustains T-cell anergy without cell death. CTLA-4 ligation …
The balance of T-cell proliferation, anergy and apoptosis is central to immune function. In this regard, co-receptor CTLA-4 is needed for the induction of anergy and tolerance. One central question concerns the mechanism by which CTLA-4 can induce T-cell non-responsiveness without a concurrent induction of antigen induced cell death (AICD). In this study, we show that CTLA-4 activation of the phosphatidylinositol 3-kinase (PI 3-K) and protein kinase B (PKB/AKT) sustains T-cell anergy without cell death. CTLA-4 ligation induced PI 3K activation as evidenced by the phosphorylation of PKB/AKT that in turn inactivated GSK-3. The level of activation was similar to that observed with CD28. CTLA-4 induced PI 3K and AKT activation also led to phosphorylation of the pro-apoptotic factor BAD as well as the up-regulation of BcL-XL. In keeping with this, CD3/CTLA-4 co-ligation prevented apoptosis under the same conditions where T-cell non-responsiveness was induced. This effect was PI 3K and PKB/AKT dependent since inhibition of these enzymes under conditions of anti-CD3/CTLA-4 co-ligation resulted in cell death. Our findings therefore define a mechanism by which CTLA-4 can induce anergy (and possibly peripheral tolerance) by preventing the induction of cell death.
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