B7-2 blockade enhances T cell responses to Leishmania donovani.
Infection with Leishmania donovani has been reported to induce a dominant Th1-type response in all strains of mice examined, providing a model for examining the regulation of Th1 responses in the relative absence of Th2 cross-regulation. Here we demonstrate that blockade of the costimulatory molecule B7-2, but not B7-1, has significant effects on disease progression, measured as day 28 parasite burden in the liver. The effects of B7-2 blockade were associated with increased IFN-gamma production, as determined 1) following restimulation with specific Ag, 2) by enumeration of IFN-gamma-secreting cells using ELISPOT assays, and 3) by analysis of IFN-gamma mRNA by reverse transcription-PCR. Surprisingly, IL-4-producing cells were also readily detected in infected mice by ELISPOT analysis. The frequency of these IL-4-producing cells and of IL-4 mRNA levels was also enhanced in the liver of infected mice treated with anti-B7-2 mAb. Administration of anti-B7-2 from the day of infection or delaying its administration until day 3 after infection had similar effects. Parasite-specific IgG1 and IgG2a responses were either unaffected or marginally increased following anti-B7-2 administration, contrary to the inhibitory effect of this treatment on responses to the T-dependent Ag DNP-BSA. These data support a model of T cell activation whereby B7-2/CD28 interactions play a relatively redundant role in initial T cell activation, but in which interference with later B7-2/CTLA4 interaction potentiates established cytokine responses.
Murphy
M L
ML
Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, United Kingdom.
Engwerda
C R
CR
Gorak
P M
PM
Kaye
P M
PM
D000818:Animals; D015703:Antigens, CD / Q000276:immunology*; D000953:Antigens, Protozoan / Q000276:immunology*; D051940:B7-2 Antigen; D005260:Female; D007111:Immunity, Cellular; D015847:Interleukin-4 / Q000276:immunology; D007893:Leishmania donovani / Q000276:immunology*; D007898:Leishmaniasis, Visceral / Q000276:immunology*; D008562:Membrane Glycoproteins / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D018417:Th1 Cells / Q000276:immunology* / Q000469:parasitology; D018418:Th2 Cells / Q000276:immunology* / Q000469:parasitology
D015703:Antigens, CD; D000953:Antigens, Protozoan; D051940:B7-2 Antigen; C497965:Cd86 protein, mouse; D008562:Membrane Glycoproteins; D015847:Interleukin-4