Th1 development of naive CD4+ T cells is inhibited by co-activation with anti-CD4 monoclonal antibodies.
Co-activation of CD4+ T cells by anti-CD4 mAb strongly enhances the proliferation of these T cells. We have analyzed the influence of CD4-mediated co-activation on Th cell differentiation. Our data demonstrate that activation of high density (HD)-CD4+ T cells by immobilized anti-CD3 mAb in combination with immobilized anti-CD4 mAb led to a strong inhibition of Th1 differentiation and to a variable but significant induction of Th2 development. Priming of highly enriched Mel-14highCD4+ T cells in the presence of anti-CD4 mAb also resulted in a pronounced suppression of secondary IFN-gamma production, indicating that the Th1 development of naive CD4+ T cells is inhibited by co-activation via CD4. In contrast to HD-CD4+ T cells, CD4-induced costimulation of MEL-14highCD4+ T cells did not result in a primary and secondary IL-4 production. Hence, these results suggest that a MEL-14low population within the HD-CD4+ T cell fraction was the source of the endogenous IL-4 and imply, in addition, that co-activation via CD4 inhibits the development of Th1 cells from naive CD4+ T cells independently from endogenous IL-4. This assumption is further corroborated by the fact that neither the application of neutralizing anti-IL-4 mAb nor the use of T cells from IL-4 knockout mice could prevent CD4-mediated inhibition of Th1 development. The Th1-inhibiting effect of anti-CD4 mAb could not be reversed by the application of the Th1 inducer IL-12. On the contrary, the secondary IL-4 production of HD-CD4+ T cells as an indicator of Th2 differentiation, which was promoted by anti-CD4 mAb, was enhanced even in the presence of IL-12. Therefore, our results suggest that co-activation of naive CD4+ T cells by anti-CD4 mAb directly and selectively inhibits Th1 differentiation of naive dense CD4+ T cells.
Goedert
S
S
Institute for Immunology, Johannes Gutenberg University, Mainz, Germany.
Germann
T
T
Hoehn
P
P
Koelsch
S
S
Palm
N
N
Rüde
E
E
Schmitt
E
E
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D017252:CD3 Complex / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology*; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D004357:Drug Synergism; D005260:Female; D006131:Growth Inhibitors / Q000276:immunology* / Q000494:pharmacology; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D018664:Interleukin-12 / Q000494:pharmacology; D015847:Interleukin-4 / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008817:Mice, Mutant Strains; D018417:Th1 Cells / Q000276:immunology*
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D015704:CD4 Antigens; D006131:Growth Inhibitors; D007166:Immunosuppressive Agents; D018664:Interleukin-12; D015847:Interleukin-4; D007371:Interferon-gamma