Control of Toxoplasma reactivation by rescue of dysfunctional CD8⁺ T-cell response via PD-1—PDL-1 blockade

In this study, we document that Toxoplasma gondii differentiation and reactivation are mediated by systemic CD8 T-cell dysfunction during chronic infection. We demonstrate that CD8⁺ T-cell exhaustion occurs despite control of parasitemia during early-chronic toxoplasmosis. During later phases, these...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2011-05, Vol.108 (22), p.9196-9201
Main Authors: Bhadra, Rajarshi, Gigley, Jason P., Weiss, Louis M., Khan, Imtiaz A.
Format: Article
Language:English
Subjects:
Adaptive Immunity
Animals
Antibodies
Antigens
Antigens, Differentiation - metabolism
Apoptosis
B7-1 Antigen - metabolism
B7-H1 Antigen
Biological Sciences
Blood
CD8 antigen
CD8-Positive T-Lymphocytes - metabolism
Cell Differentiation
Chronic infection
Differentiation
Gene expression
Humans
Infections
Leukocytes
Lymphatic system
Lymphocyte Activation
Lymphocytes T
Membrane Glycoproteins - metabolism
Mice
Mice, Inbred C57BL
Models, Biological
Mortality
parasitemia
Parasites
Parasitic protozoa
Parasitism
Pathogens
PD-1 protein
Peptides - metabolism
Programmed Cell Death 1 Receptor
Receptors, Immunologic - metabolism
Studies
T cell receptors
T lymphocytes
Toxoplasma - immunology
Toxoplasma gondii
Toxoplasmosis
Toxoplasmosis - immunology
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Summary:In this study, we document that Toxoplasma gondii differentiation and reactivation are mediated by systemic CD8 T-cell dysfunction during chronic infection. We demonstrate that CD8⁺ T-cell exhaustion occurs despite control of parasitemia during early-chronic toxoplasmosis. During later phases, these cells become exhausted, leading to parasite reactivation and mortality. Concomitant with increased CD8⁺ T-cell apoptosis and decreased effector response, this dysfunction is characterized by a graded elevation in expression of inhibitory receptor PD-1 on these cells in both lymphoid and nonlymphoid tissue. Blockade of the PD-1—PDL-1 pathway reinvigorates this suboptimal CD8⁺ T-cell response, resulting in control of parasite reactivation and prevention of mortality in chronically infected animals. To the best of our knowledge, this report is unique in showing that exposure to a persistent pathogen despite initial control of parasitemia can lead to CD8⁺ T-cell dysfunction and parasite reactivation.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.1015298108