Contribution of interleukin-12 (IL-12) and the CD28/B7 and CD40/CD40 ligand pathways to the development of a pathological T-cell response in IL-10-deficient mice.
The ability of interleukin-10 (IL-10) to suppress accessory cell functions required for optimal T-cell activation makes it an important inhibitor of cell-mediated immunity. Thus, after infection with the protozoan parasite Toxoplasma gondii, IL-10 knockout (KO) mice develop a CD4(+)-T-cell-dependent shock-like reaction with high levels of IL-12 and gamma interferon (IFN-gamma) in serum, leading to death of mice during the acute phase of infection. Previous studies from this laboratory have shown that simultaneous blockade of CD28 and CD40 can prevent this lethal reaction by inhibiting the production of IFN-gamma. However, the blockade of costimulation did not affect systemic levels of IL-12. To better understand the relationship between IL-12 and the CD28 and CD40 pathways in mediating immune hyperactivity, antagonists of these factors were used to determine their effects on the development of a pathological T-cell response in IL-10 KO mice. Blockade of IL-12 or the CD28/B7 interaction alone did not affect survival; however, the combined blockade of both pathways resulted in decreased production of IFN-gamma and the survival of IL-10 KO mice. To assess the role of the two ligands for CD28, B7.1 and B7.2, IL-10 KO mice were treated with alphaIL-12 plus alphaB7.1 or alphaB7.2 or the combination of all three antibodies. These studies revealed that blockade of both B7 molecules is required for decreased production of IFN-gamma and survival of infected IL-10 KO mice, suggesting that B7.1 and B7.2 can contribute to the lethal shock-like reaction in IL-10 KO mice. In contrast, neutralization of IL-12 and blockade of the CD40/CD40 ligand (CD40L) interaction in vivo did not alter the production of IFN-gamma and only resulted in a small delay in time to death of mice. Together, these data suggest that the CD28/B7 interaction has a central role in the development of a pathological T-cell response in IL-10 KO mice, which is distinct from the role of the CD40/CD40L and IL-12 pathways.
Wille
Ulrike
U
School of Veterinary Medicine, University of Pennsylvania, Philadelphia 19104, USA.
Villegas
Eric N
EN
Craig
Linden
L
Peach
Robert
R
Hunter
Christopher A
CA
D000818:Animals; D018122:B7-1 Antigen / Q000378:metabolism; D018106:CD28 Antigens / Q000378:metabolism*; D019013:CD40 Antigens / Q000378:metabolism; D023201:CD40 Ligand / Q000378:metabolism; D005260:Female; D016753:Interleukin-10 / Q000235:genetics / Q000276:immunology*; D018664:Interleukin-12 / Q000378:metabolism*; D008099:Liver / Q000473:pathology; D051379:Mice; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology*; D014122:Toxoplasma / Q000472:pathogenicity*; D014124:Toxoplasmosis, Animal / Q000276:immunology* / Q000469:parasitology / Q000473:pathology / Q000503:physiopathology
D018122:B7-1 Antigen; D018106:CD28 Antigens; D019013:CD40 Antigens; D016753:Interleukin-10; D023201:CD40 Ligand; D018664:Interleukin-12