In vivo CD40-gp39 interactions are essential for thymus-dependent humoral immunity. II. Prolonged suppression of the humoral immune response by an antibody to the ligand for CD40, gp39.
The ligand for CD40 has been recently identified as a 39-kd protein, gp39, expressed on the surface of activated CD4+ T helper cells (Th). In vitro, soluble CD40 and anti-gp39 have been shown to block the ability of Th to activate B cells, suggesting that gp39-CD40 interactions are important to T cell-dependent B cell activation. Here it is shown that in vivo administration of anti-gp39 dramatically reduced both primary and secondary humoral immune responses to erythrocytes and soluble protein antigens without altering responses to the T-independent type II antigen, trinitrophenyl-Ficoll. Treatment of mice for 4 d with anti-gp39 inhibited the anti-sheep red blood cell (SRBC) response for at least 3 wk and inhibited the expression of all immunoglobulin isotypes in secondary responses to the protein antigen, keyhole limpet hemocyanin. To examine the direct effect of anti-gp39 on Th function, SRBC-immune Th cells from anti-gp39-treated mice were adoptively transferred and shown to be fully capable of providing help. These results suggest that anti-gp39 treatment does not cause Th deletion or anergy. Anti-gp39 may mediate its profound immunosuppressive effects on humoral immunity by blocking gp39-CD40 interactions. Moreover, these studies establish gp39-CD40 as an important receptor-ligand pair for the targeting of therapeutic antibodies to control thymus-dependent humoral responses.
Foy
T M
TM
Department of Microbiology, Dartmouth Medical School, Lebanon, New Hampshire 03756.
Shepherd
D M
DM
Durie
F H
FH
Aruffo
A
A
Ledbetter
J A
JA
Noelle
R J
RJ
D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D000917:Antibody Formation; D015703:Antigens, CD / Q000276:immunology* / Q000378:metabolism*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000276:immunology* / Q000378:metabolism*; D001402:B-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens; D023201:CD40 Ligand; D002999:Clone Cells; D006224:Cricetinae / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006433:Hemocyanins / Q000276:immunology; D006801:Humans; D007073:Immunoglobulin E / Q000032:analysis / Q000096:biosynthesis; D007074:Immunoglobulin G / Q000032:analysis / Q000096:biosynthesis / Q000145:classification; D007075:Immunoglobulin M / Q000032:analysis / Q000096:biosynthesis; D007165:Immunosuppression Therapy; D016219:Immunotherapy, Adoptive; D008562:Membrane Glycoproteins / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D013601:T-Lymphocytes / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D013950:Thymus Gland / Q000276:immunology*
D000906:Antibodies; D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D019013:CD40 Antigens; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; D007073:Immunoglobulin E; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin