Th2-dependent B cell responses in the absence of CD40-CD40 ligand interactions.
CD40 is thought to play a central role in T cell-dependent humoral responses through two distinct mechanisms. CD4+ T helper cells are activated via CD40-dependent Ag presentation in which CD80/CD86 provides costimulation through CD28. In addition, engagement of CD40 on B cells provides a direct pathway for activation of humoral responses. We used a model of adenovirus-mediated gene transfer of beta-galactosidase (lacZ) into murine lung to evaluate the specific CD40-dependent pathways required for humoral immunity at mucosal surfaces of the lung. Animals deficient in CD40L failed to develop T and B cell responses to vector. Activation of Th2 cells, which normally requires CD40-dependent stimulation of APCs, was selectively reconstituted in CD40 ligand-deficient mice by systemic administration of an Ab that is agonistic to CD28. Surprisingly, this resulted in the development of a functional humoral response to vector as evidenced by formation of germinal centers and production of antiadenovirus IgG1 and IgA that neutralized and prevented effective readministration of vector. The CD28-dependent B cell response required CD4+ T cells and was mediated via IL-4. These studies indicate that CD40 signals to the B cells are not necessary for CD4+ Th2 cell-dependent humoral responses to be generated.
Chirmule
N
N
Institute for Human Gene Therapy, Department of Molecular Engineering, University of Pennsylvania, Philadelphia 19104, USA.
Tazelaar
J
J
Wilson
J M
JM
D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D018106:CD28 Antigens / Q000502:physiology; D019013:CD40 Antigens / Q000235:genetics* / Q000378:metabolism* / Q000502:physiology; D023201:CD40 Ligand; D002469:Cell Separation; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D005822:Genetic Vectors / Q000276:immunology; D006801:Humans; D015847:Interleukin-4 / Q000502:physiology; D008024:Ligands; D008213:Lymphocyte Activation / Q000235:genetics; D008562:Membrane Glycoproteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology*
D000914:Antibodies, Viral; D018106:CD28 Antigens; D019013:CD40 Antigens; D008024:Ligands; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; D015847:Interleukin-4