B7-H1 blockade increases survival of dysfunctional CD8(+) T cells and confers protection against Leishmania donovani infections

PLoS Pathog. 2009 May;5(5):e1000431. doi: 10.1371/journal.ppat.1000431. Epub 2009 May 15.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Genetically Modified
  • Antigens, CD / metabolism
  • B7-1 Antigen / immunology
  • B7-1 Antigen / metabolism*
  • B7-H1 Antigen
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Proliferation
  • Cloning, Molecular
  • Dendritic Cells / immunology
  • Dendritic Cells / metabolism
  • Disease Models, Animal
  • Leishmania donovani / immunology
  • Leishmania donovani / pathogenicity*
  • Leishmaniasis, Visceral / immunology*
  • Leishmaniasis, Visceral / parasitology
  • Lymphocyte Activation
  • Membrane Glycoproteins / immunology
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Ovalbumin / immunology
  • Peptide Fragments / immunology
  • Peptides / immunology
  • Peptides / metabolism*
  • Spleen / parasitology
  • Superinfection
  • Vaccinia virus / genetics
  • Vaccinia virus / immunology

Substances

  • Antigens, CD
  • B7-1 Antigen
  • B7-H1 Antigen
  • Cd274 protein, mouse
  • Membrane Glycoproteins
  • OVA-8
  • Peptide Fragments
  • Peptides
  • Ovalbumin