CD28 provides T-cell costimulation and enhances PI3K activity at the immune synapse independently of its capacity to interact with the p85/p110 heterodimer

Author:

Garçon Fabien1,Patton Daniel T.1,Emery Juliet L.1,Hirsch Emilio2,Rottapel Robert3,Sasaki Takehiko4,Okkenhaug Klaus1

Affiliation:

1. Laboratory of Lymphocyte Signaling and Development, Babraham Institute, Babraham Research Campus, Cambridge, United Kingdom;

2. Department of Genetics, Biology and Biochemistry, University of Turin, Turin, Italy;

3. Princess Margaret Hospital/Ontario Cancer Institute, Toronto, ON;

4. Department of Pathology and Immunology, Akita University School of Medicine, Akita, Japan

Abstract

Abstract Activation of PI3K is among the earliest signaling events observed in T cells after conjugate formation with antigen-presenting cells (APCs). The relevant PI3K catalytic isoform and relative contribution of the TcR and CD28 to PI3K activity at the immune synapse have not been determined unequivocally. Using a quantitative imaging-based assay, we show that the PI3K activity at the T cell–APC contact area is dependent on the p110δ, but not the p110γ, isoform of PI3K. CD28 enhanced PIP3 production at the T-cell synapse independently of its YMNM PI3K-recruitment motif that instead was required for efficient PKCθ recruitment. CD28 could partially compensate for the lack of p110δ activity during T-cell activation, which indicates that CD28 and p110δ act in parallel and complementary pathways to activate T cells. Consistent with this, CD28 and p110δ double-deficient mice were severely immune compromised. We therefore suggest that combined pharmaceutic targeting of p110δ activity and CD28 costimulation has potent therapeutic potential.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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