Disparate functions of I-A and I-E molecules on B cells as evidenced by the inhibition with anti-I-A and anti-I-E antibodies of polyclonal B cell activation.
Polyclonal differentiation of unprimed B cells into IgM-producing cells induced by lipopolysaccharide (LPS) or T cell-derived lymphokine B151-TRF2 has been shown to contain a process of I-A-restricted B-B cell interaction, so that the B cell responses are inhibited by monoclonal antibodies (mAb) specific for I-A molecules. On the other hand, the B cell responses are also inhibited by anti-I-E mAb, although I-E molecules are not involved in such B-B cell interaction. In this study, we examined the mechanism underlying the anti-I-E-mediated inhibition of the B cell responses. The B cell responses induced by LPS or B151-TRF2 were inhibited by either anti-I-A or anti-I-E mAb added on day 0 over a 5-day culture period, whereas when added on day 3 the responses were inhibited only by anti-I-E mAb and not by anti-I-A mAb. To gain insight into the mechanism underlying the anti-I-E-mediated inhibition, we prepared monovalent Fab and divalent F(ab')2 fragments of anti-I-A and anti-I-E mAb and examined their effects on the B cell responses. We found that the B cell responses were inhibited by the F(ab')2 but not Fab fragment of anti-I-E mAb, whereas the Fab fragment of anti-I-A mAb still gave effective inhibition. The F(ab')2 but not Fab fragment of anti-I-E mAb induced increases in cyclic AMP (cAMP) levels in B cells, whereas the undigested anti-I-A mAb did not induce such increases. Furthermore, adenylate cyclase inhibitors, which inhibit cellular cAMP accumulation, circumvented the B cell responses inhibited by anti-I-E but not anti-I-A mAb. Thus, these results indicate that the anti-I-E-mediated inhibition of the B cell responses requires increases in intracellular cAMP levels induced by cross-linking of I-E molecules. In contrast, anti-I-A mAb inhibits the B cell responses without cross-linking of I-A molecules and cAMP accumulation. These results reinforce a unique function of I-A molecules as restriction elements in the Ia-restricted B-B cell interaction.
Takahama
Y
Y
Biomedical Research Center, Osaka University Medical School, Japan.
Ono
S
S
Ishihara
K
K
Muramatsu
M
M
Hamaoka
T
T
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation; D000242:Cyclic AMP / Q000502:physiology; D000949:Histocompatibility Antigens Class II / Q000502:physiology*; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D007074:Immunoglobulin G / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008815:Mice, Inbred Strains; D008970:Molecular Weight; D011940:Receptor Aggregation; D015398:Signal Transduction; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
D000911:Antibodies, Monoclonal; D000949:Histocompatibility Antigens Class II; C024138:I-E-antigen; D007140:Immunoglobulin Fab Fragments; D007074:Immunoglobulin G; D000242:Cyclic AMP