Cyclosporin A increases IFN-gamma production by T cells when co-stimulated through CD28.
Despite its calcineurin-inhibiting properties, cyclosporin A (CsA) can not inhibit IL-2 production when T cells are co-stimulated by CD80/CD86 on the antigen-presenting cells. We studied the in vitro effect of CsA on IFN-gamma production. Anti-CD3 monoclonal antibody (mAb) was used as the primary stimulus for activation of purified human T cells. A stimulating anti-CD28 mAb, or CD80 or CD86 on stably transfected P815 cells, provided the co-stimulatory signal. IL-2 production was hardly affected by CsA under these stimulating conditions, while IFN-gamma (at the protein and mRNA level) was markedly stimulated by CsA. The use of anti-CD3 or phorbol 12-myristate 13-acetate with ionomycin as the primary stimulus, together with costimulation through either CD28 or CD2 using transfectants with the appropriate ligands, allowed us to demonstrate that the resistance of IFN-gamma production to inhibition by CsA required both CD3 and CD28 triggering. Inhibition of IL-10 production, and to a lesser degree of IL-4 production, by CD4+ cells was responsible for the enhancement of IFN-gamma production in the presence of CsA. In conclusion, IFN-gamma production by CD28-co-stimulated CD4+ T cells is resistant to inhibition by CsA and can even be facilitated by CsA as a result of removing a negative regulatory signal which is mainly IL-10 mediated. This finding might have implications for immunosuppressive strategies based upon the use of CsA.
Rafiq
K
K
Laboratory of Experimental Immunology, Leuven, Belgium.
Kasran
A
A
Peng
X
X
Warmerdam
P A
PA
Coorevits
L
L
Ceuppens
J L
JL
Van Gool
S W
SW
D000276:Adjuvants, Immunologic / Q000494:pharmacology* / Q000502:physiology*; D000818:Animals; D018106:CD28 Antigens / Q000502:physiology*; D017252:CD3 Complex / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D016572:Cyclosporine / Q000494:pharmacology*; D004351:Drug Resistance; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics; D016753:Interleukin-10 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D007376:Interleukin-2 / Q000502:physiology; D015847:Interleukin-4 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects; D012515:Mast-Cell Sarcoma; D051379:Mice; D012333:RNA, Messenger / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000276:Adjuvants, Immunologic; D018106:CD28 Antigens; D017252:CD3 Complex; D007376:Interleukin-2; D012333:RNA, Messenger; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D016572:Cyclosporine