The antigen dose determines T helper subset development by regulation of CD40 ligand.
Although the amount of antigen and the strength of T cell stimulation have been suggested to regulate Th1 vs. Th2 polarization, it remains unclear how the antigen dose and the strength of signal is detected by the T cell and translated into differential cytokine production. Using co-cultures of dendritic cells (DC) and ovalbumin (OVA)-specific CD4+ T cells obtained from RAG-2)(-/-) DO11.10 mice, we show here that high-dose antigen induced Th1 development by up-regulation of CD40 ligand (CD40L), whereas low-dose antigen stimulation failed to induce CD40L and promoted Th2 development. CD40-CD40L interaction was essential for IL-12 production by DC. In the absence, de novo IL-4 production by T cells and autocrine Th2 development was induced. Furthermore, our results demonstrate that LFA-1/ ICAM interaction promotes Th1 differentiation by lowering the antigen dose required for CD40L up-regulation. Thus, we propose that (1) peptide-MHC density and (2) accessory molecules such as LFA-1 determine T helper polarization by regulation of CD40L.
Basel Institute for Immunology, Switzerland.
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Ruedl
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Bachmann
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M
Kopf
D000818:Animals; D019013:CD40 Antigens / Q000276:immunology; D023201:CD40 Ligand; D015815:Cell Adhesion Molecules / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D019891:Leukopoiesis; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000276:immunology* / Q000494:pharmacology; D010446:Peptide Fragments / Q000276:immunology* / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D018417:Th1 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D018418:Th2 Cells / Q000166:cytology / Q000187:drug effects / Q000276:immunology*
D019013:CD40 Antigens; D015815:Cell Adhesion Molecules; D000949:Histocompatibility Antigens Class II; D016169:Lymphocyte Function-Associated Antigen-1; D008562:Membrane Glycoproteins; C111390:OVA 323-339; D010446:Peptide Fragments; D023201:CD40 Ligand; D010047:Ovalbumin