B7-H1 blockade increases survival of dysfunctional CD8(+) T cells and confers protection against Leishmania donovani infections.
Experimental visceral leishmaniasis (VL) represents an exquisite model to study CD8(+) T cell responses in a context of chronic inflammation and antigen persistence, since it is characterized by chronic infection in the spleen and CD8(+) T cells are required for the development of protective immunity. However, antigen-specific CD8(+) T cell responses in VL have so far not been studied, due to the absence of any defined Leishmania-specific CD8(+) T cell epitopes. In this study, transgenic Leishmania donovani parasites expressing ovalbumin were used to characterize the development, function, and fate of Leishmania-specific CD8(+) T cell responses. Here we show that L. donovani parasites evade CD8(+) T cell responses by limiting their expansion and inducing functional exhaustion and cell death. Dysfunctional CD8(+) T cells could be partially rescued by in vivo B7-H1 blockade, which increased CD8(+) T cell survival but failed to restore cytokine production. Nevertheless, B7-H1 blockade significantly reduced the splenic parasite burden. These findings could be exploited for the design of new strategies for immunotherapeutic interventions against VL.
Joshi
Trupti
T
Department of Pharmacology and Molecular Sciences, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Rodriguez
Susana
S
Perovic
Vladimir
V
Cockburn
Ian A
IA
Stäger
Simona
S
D000818:Animals; D030801:Animals, Genetically Modified; D015703:Antigens, CD / Q000378:metabolism; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism*; D060890:B7-H1 Antigen; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D003001:Cloning, Molecular; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D007893:Leishmania donovani / Q000276:immunology / Q000472:pathogenicity*; D007898:Leishmaniasis, Visceral / Q000276:immunology* / Q000469:parasitology; D008213:Lymphocyte Activation; D008562:Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D010455:Peptides / Q000276:immunology / Q000378:metabolism*; D013154:Spleen / Q000469:parasitology; D015163:Superinfection; D014616:Vaccinia virus / Q000235:genetics / Q000276:immunology
D015703:Antigens, CD; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008562:Membrane Glycoproteins; C110366:OVA-8; D010446:Peptide Fragments; D010455:Peptides; D010047:Ovalbumin