Blocking the CD40L-CD40 interaction in vivo specifically prevents the priming of T helper 1 cells through the inhibition of interleukin 12 secretion.
The recent finding that CD40L on activated T cells induces interleukin (IL) 12 secretion in human peripheral blood monocytes in vitro suggests that the CD40L-CD40 interaction may be of importance in the priming of T helper (Th) 1-type T cells. We therefore investigated the in vivo relevance of this interaction in an experimental model for a Th1-mediated disease, the hapten reagent (2,4,6-trinitrobenzene sulfonic acid [TNBS])-induced colitis. The administration of anti-gp39 (CD40L) antibodies during the induction phase of the Th1 response prevented interferon gamma production by lamina propria CD4+ T cells and also clinical and histological evidence of disease. In contrast, the secretion of IL-4, a Th2-type cytokine, was increased after anti-gp39 treatment. In further studies we showed that the prevention of disease activity was caused by an inhibition of IL-12 secretion, as demonstrated by immunohistochemistry. In addition, the injection of recombinant IL-12 p70 heterodimer into TNBS + anti-gp39-treated mice reversed the effect of anti-gp39 and resulted in severe disease activity. When anti-gp39 was given after the disease was established, no effect on the disease activity was observed. In conclusion, we demonstrated that the CD40L-CD40 interaction is crucial for the in vivo priming of Th1 T cells via the stimulation of IL-12 secretion by antigen-presenting cells (APC).
Stuber
E
E
Mucosal Immunity Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892-1890, USA.
Strober
W
W
Neurath
M
M
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D023201:CD40 Ligand; D003092:Colitis / Q000139:chemically induced / Q000209:etiology / Q000276:immunology* / Q000517:prevention & control; D003106:Colon / Q000276:immunology / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D018664:Interleukin-12 / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D011485:Protein Binding; D018417:Th1 Cells / Q000276:immunology*; D014302:Trinitrobenzenesulfonic Acid / Q000494:pharmacology
D000906:Antibodies; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; D018664:Interleukin-12; D014302:Trinitrobenzenesulfonic Acid