Submitted April 22, 2008
Accepted January 15, 2009
p85
phosphoinositide 3-kinase regulates CD28 co-receptor function
Isabela Alcazar, Isabel Cortes, Angel Zaballos, Carmen Hernandez, David A. Fruman, Domingo F. Barber, and Ana C. Carrera*
Department of Immunology and Oncology, Centro Nacional de Biotecnologia/CSIC, Madrid, Spain
Department of Molecular Biology & Biochemistry, and Center for Immunology, University of California Irvine, Irvine, CA, United States
* Corresponding author; email: acarrera{at}cnb.csic.es.
CD28 is a receptor expressed on T cells that regulates their differentiation following antigen-stimulation to long-term-survival memory T cells. CD28 enhances T cell-receptor signals and reduces expression of CBL ubiquitin ligases, which negatively control T cell activation. In the absence of CD28 ligation during the primary stimulation, CBL levels remain high and T cells fail to mount an efficient secondary response. CD28 associates with p85
,one of the regulatory subunits of phosphoinositide-3-kinase (PI3K), but the relevance of this interaction is debated. We examined here the contribution of the other ubiquitous PI3K regulatory subunit, p85
, in CD28 function. We describe that p85 bound to CD28 and to CBL with greater affinity than p85. Moreover, deletion of p85 impaired CD28-induced intracellular events, including c-CBL and CBL-b downregulation as well as PI3K pathway activation. This resulted in defective differentiation of activated T cells, which failed to exhibit an efficient secondary immune response. Considering that p85-deficient T cells fail in recall responses and that p85 binds to and regulates CD28 signals, the presented observations suggest the involvement of p85 in CD28-mediated activation and differentiation of antigen-stimulated T cells.
