Abstract
Although CD4 T cells are required for host resistance to Mycobacterium tuberculosis, they may also contribute to pathology. In this study, we examine the role of the inhibitory receptor PD-1 and its ligand PD-L1 during M. tuberculosis infection. After aerosol exposure, PD-1 knockout (KO) mice develop high numbers of M. tuberculosis-specific CD4 T cells but display markedly increased susceptibility to infection. Importantly, we show that CD4 T cells themselves drive the increased bacterial loads and pathology seen in infected PD-1 KO mice, and PD-1 deficiency in CD4 T cells is sufficient to trigger early mortality. PD-L1 KO mice also display enhanced albeit less severe susceptibility, indicating that T cells are regulated by multiple PD ligands during M. tuberculosis infection. M. tuberculosis-specific CD8 T cell responses were normal in PD-1 KO mice, and CD8 T cells only had a minor contribution to the exacerbated disease in the M. tuberculosis-infected PD-1 KO and PD-L1 KO mice. Thus, in the absence of the PD-1 pathway, M. tuberculosis benefits from CD4 T cell responses, and host resistance requires inhibition by PD-1 to prevent T cell-driven exacerbation of the infection.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Aerosols
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Animals
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Antigens, Surface / metabolism
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Antigens, Surface / physiology*
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Apoptosis Regulatory Proteins / deficiency*
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Apoptosis Regulatory Proteins / metabolism
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Apoptosis Regulatory Proteins / physiology*
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B7-1 Antigen / metabolism
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B7-1 Antigen / physiology
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B7-H1 Antigen
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CD4 Lymphocyte Count
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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CD4-Positive T-Lymphocytes / microbiology*
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / pathology
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Epitopes, T-Lymphocyte / genetics
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Epitopes, T-Lymphocyte / immunology
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Genetic Predisposition to Disease
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Membrane Glycoproteins / metabolism
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Membrane Glycoproteins / physiology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Mycobacterium tuberculosis / growth & development
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Mycobacterium tuberculosis / immunology*
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Necrosis
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Peptides / metabolism
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Peptides / physiology
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Programmed Cell Death 1 Receptor
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Tuberculosis, Pulmonary / immunology*
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Tuberculosis, Pulmonary / pathology*
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Tuberculosis, Pulmonary / prevention & control
Substances
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Aerosols
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Antigens, Surface
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Apoptosis Regulatory Proteins
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B7-1 Antigen
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B7-H1 Antigen
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Cd274 protein, mouse
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Epitopes, T-Lymphocyte
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Membrane Glycoproteins
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Pdcd1 protein, mouse
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Peptides
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Programmed Cell Death 1 Receptor