CD40 ligand signals optimize T helper cell cytokine production: role in Th2 development and induction of germinal centers.
The role of CD40 in the development of germinal centers (GC) is not simply to initiate the B cell response, as rudimentary GC can develop in CD40-/- mice that are injected with CD40-immunoglobulin (Ig) fusion protein. This indicates that CD40 ligand (CD40L) transduces a signal to T cells that is important in the process. In this study we have used an in vitro model of GC development to investigate the role of CD40L, cytokines and other co-stimuli. The model involves the specific induction of an H-2E transgene in GC B cells (in Sma58 mice). We find that Th2 cytokines together with Ig and CD40 cross-linking are the most efficient means of induction of the GC phenotype. Although IL-4 plays some inductive role, it is not the sole active ingredient in the mix of cytokines made by Th2 cells. Our studies on primary T cells and T cell clones activated in the absence of CD40 on antigen-presenting cells or CD40L on T cells indicate that the CD40L co-stimulus does not directly bias the response to Th2 cells, as previously reported, but that it augments terminal effector T cell differentiation or the level of secretory activity. However, both in vitro and in vivo, the CD40L co-stimulus is crucially important for Th2 development as in its absence IL-4 production is suboptimal and does not compete with a larger, more rapid IFN-gamma response.
Poudrier
J
J
Department of Immunology, Imperial College School of Medicine, London, GB.
van Essen
D
D
Morales-Alcelay
S
S
Leanderson
T
T
Bergthorsdottir
S
S
Gray
D
D
D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology; D023201:CD40 Ligand; D003432:Cross-Linking Reagents; D018858:Germinal Center / Q000502:physiology*; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis*; D015847:Interleukin-4 / Q000096:biosynthesis* / Q000502:physiology; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018448:Models, Immunological; D015398:Signal Transduction; D018417:Th1 Cells / Q000502:physiology; D018418:Th2 Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*
D003432:Cross-Linking Reagents; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; D015847:Interleukin-4; D007371:Interferon-gamma