Modeling of T cell contact-dependent B cell activation. IL-4 and antigen receptor ligation primes quiescent B cells to mobilize calcium in response to Ia cross-linking.
The generation of antibody secretory cells from resting B lymphocytes after immunization with most protein Ag requires B cell signaling by Ag, direct Th cell contact and lymphokines. Previous studies suggest that cell contact-mediated signals may be transduced by Ia after Ia binding by alpha beta TCR and/or CD4. Seemingly inconsistent with this concept are findings that cross-linking of Ia molecules on quiescent B cells leads to cAMP generation that is antagonistic for B cell mitogenesis. Here we show that ligand binding to IL-4 and Ag receptors on quiescent B cells induce transition of these cells into a competent state in which Ia molecules transduce signals via a distinct mechanism. This mechanism involves the tyrosine kinase-dependent activation of phospholipase C leading to Ca2+ mobilization from intracellular stores and the extracellular space. This competence, which is seen within 4 h of priming, is not simply a function of increased Ia expression by the B cell because the response can be induced by cross-linking of less than 5% of cell surface Ia molecules on primed cells. Finally, cross-linking of Ia molecules leads to more than fivefold greater increase in [Ca2+]i than is induced by membrane Ig ligation. These findings are consistent with alpha beta TCR/CD4 delivery via Ia of proliferative signals mediated by tyrosine kinase activation, phosphoinositide hydrolysis and Ca2+ mobilization.
Cambier
J C
JC
Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206.
Morrison
D C
DC
Chien
M M
MM
Lehmann
K R
KR
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D016227:Benzoquinones; D002118:Calcium / Q000502:physiology*; D019833:Genistein; D000949:Histocompatibility Antigens Class II / Q000502:physiology*; D066298:In Vitro Techniques; D047029:Lactams, Macrocyclic; D008213:Lymphocyte Activation; D008211:Lymphocyte Cooperation; D051379:Mice; D008815:Mice, Inbred Strains; D010716:Phosphatidylinositols / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011809:Quinones / Q000494:pharmacology; D011940:Receptor Aggregation; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen / Q000502:physiology*; D017828:Rifabutin / Q000031:analogs & derivatives; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D016227:Benzoquinones; D000949:Histocompatibility Antigens Class II; D047029:Lactams, Macrocyclic; D010716:Phosphatidylinositols; D011809:Quinones; D011947:Receptors, Antigen, B-Cell; D019948:Receptors, Interleukin-4; D011975:Receptors, Mitogen; D017828:Rifabutin; C020754:herbimycin; D019833:Genistein; D011505:Protein-Tyrosine Kinases; D002118:Calcium