p85β phosphoinositide 3-kinase regulates CD28 coreceptor function

CD28 is a receptor expressed on T cells that regulates their differentiation after 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 alpha, 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 beta, in CD28 function. We describe that p85 beta bound to CD28 and to CBL with greater affinity than p85 alpha. Moreover, deletion of p85 beta impaired CD28-induced intracellular events, including c-CBL and CBL-b down-regulation 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 beta-deficient T cells fail in recall responses and that p85 beta binds to and regulates CD28 signals, the presented observations suggest the involvement of p85 beta in CD28-mediated activation and differentiation of antigen-stimulated T cells. (Blood. 2009; 113:3198-3208)