p85beta 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 p85alpha, 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, p85beta, in CD28 function. We describe that p85beta bound to CD28 and to CBL with greater affinity than p85alpha. Moreover, deletion of p85beta 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 p85beta-deficient T cells fail in recall responses and that p85beta binds to and regulates CD28 signals, the presented observations suggest the involvement of p85beta in CD28-mediated activation and differentiation of antigen-stimulated T cells.
Alcázar
Isabela
I
Department of Immunology and Oncology, Centro Nacional de Biotecnología/CSIC, Madrid, Spain.
Cortés
Isabel
I
Zaballos
Angel
A
Hernandez
Carmen
C
Fruman
David A
DA
Barber
Domingo F
DF
Carrera
Ana C
AC
D019870:1-Phosphatidylinositol 4-Kinase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D018106:CD28 Antigens / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D056827:Endosomal Sorting Complexes Required for Transport; D005786:Gene Expression Regulation; D019672:Genes, T-Cell Receptor; D006801:Humans; D007527:Isoenzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D000075702:Nedd4 Ubiquitin Protein Ligases; D011485:Protein Binding / Q000502:physiology; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000502:physiology; D018909:src Homology Domains
D018106:CD28 Antigens; D056827:Endosomal Sorting Complexes Required for Transport; D007527:Isoenzymes; D000075702:Nedd4 Ubiquitin Protein Ligases; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases; D019870:1-Phosphatidylinositol 4-Kinase; C493849:Cbl protein, mouse