Dynamics of MHC class II-activating signals in murine resting B cells.
MHC class II (MHC II) proteins are competent signaling molecules on APC. However, little is known about the mechanisms that control generation of their activating signals. Previous reports highlighted a number of factors that could affect the nature and outcome of MHC II signals, including the inability of MHC II ligation on resting vs activated murine B cells to induce mobilization of Ca2+. In the present study, we report that ligation of MHC II on resting murine B cells reproducibly induces mobilization of intracellular Ca2+ using both mAbs and cognate T cells as ligands. Mobilization of Ca2+ was independent of MHC II haplotype, isotype, or mouse genetic background. MHC II-mediated mobilization of Ca2+ is completely inhibited by inhibitors of src-like kinases and syk, and MHC II ligation increases overall tyrosine phosphorylation level. Moreover, MHC II ligation results in specific up-regulation of CD86. However, induction of these responses is dependent on the type of anti-MHC II Ab used, suggesting that epitope specificity and/or the nature of ligation is important. Moreover, we demonstrate that MHC II-derived signals are strictly regulated by the order and timing of BCR and CD40 signals, suggesting coordination of these signals preserves the integrity of early B cell priming events. Thus, the mode and the context of MHC II ligation influence generation of MHC II-derived activating signals in resting B cells. Based on these results, a new model that highlights the role of MHC II-activating signals in regulation of Ag presentation by B cells is proposed.
Nashar
Toufic O
TO
Albany Medical College, Center for Immunology and Microbial Disease, Albany, NY 12208, USA.
Drake
James R
JR
D000818:Animals; D000911:Antibodies, Monoclonal; D001402:B-Lymphocytes / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D020013:Calcium Signaling; D006239:Haplotypes; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D018448:Models, Immunological; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D016192:Resting Phase, Cell Cycle; D015398:Signal Transduction; D000072377:Syk Kinase; D013601:T-Lymphocytes / Q000276:immunology; D019061:src-Family Kinases / Q000378:metabolism
D000911:Antibodies, Monoclonal; D051940:B7-2 Antigen; D000949:Histocompatibility Antigens Class II; D047908:Intracellular Signaling Peptides and Proteins; D011947:Receptors, Antigen, B-Cell; D011505:Protein-Tyrosine Kinases; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D019061:src-Family Kinases