Requirement for phosphoinositide 3-kinase p110delta signaling in B cell antigen receptor-mediated antigen presentation.
The BCR serves to both signal cellular activation and enhance uptake and presentation of Ags by B cells; however, the intracellular signaling mechanisms linking the BCR to Ag presentation functions have been controversial. PI3Ks are critical signaling enzymes controlling many cellular processes, with the p110delta isoform playing a critical role in BCR signaling. In this study, we used pharmacological and genetic approaches to evaluate the role of p110delta signaling in Ag presentation by primary B lymphocytes. It was found that activation of allogeneic T cells is significantly reduced when B cells are pretreated with global PI3K inhibitors, but was intact when p110delta signaling was specifically inactivated. In contrast, inactivation of p110delta significantly impaired the ability of B cells to activate T cells in a BCR-mediated Ag uptake and presentation model. Prestimulation of p110delta-inactivated B cells with anti-CD40 or LPS could not rescue their BCR-mediated Ag presentation ability to normal levels. p110delta signaling was required for efficient presentation of either anti-Ig or protein Ag via a lysozyme-specific BCR. p110delta-inactivated B cells were able to internalize Ag normally, and no defects in association of Ag with lysosome-associated membrane protein 1(+) late endosomes were observed; however, these cells were less effective in forming polarized conjugates with Ag-specific T cells. Our data demonstrate a role for p110delta signaling in B cell Ag presentation function, implicating 3-phosphoinositides and their targets in the latter stages of this process.
Al-Alwan
Monther M
MM
Department of Immunology, University of Manitoba, Winnipeg, Canada.
Okkenhaug
Klaus
K
Vanhaesebroeck
Bart
B
Hayflick
Joel S
JS
Marshall
Aaron J
AJ
D000818:Animals; D017951:Antigen Presentation / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D002478:Cells, Cultured; D058534:Class I Phosphatidylinositol 3-Kinases; D011992:Endosomes / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology*; D008247:Lysosomes / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology*; D051562:Proto-Oncogene Proteins c-bcr / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology
D019869:Phosphatidylinositol 3-Kinases; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases; C496614:Bcr protein, mouse; D051562:Proto-Oncogene Proteins c-bcr