title: CD4 T cells promote rather than control tuberculosis in the absence of PD-1-mediated inhibition.
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.
authors.affiliation: Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. barberd@niaid.nih.gov
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Barber
authors.forename: Katrin D
authors.initials: KD
authors.lastname: Mayer-Barber
authors.forename: Carl G
authors.initials: CG
authors.lastname: Feng
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: Alan
authors.initials: A
authors.lastname: Sher
mesh_terms: D000336:Aerosols; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency* / Q000378:metabolism / Q000502:physiology*; D018122:B7-1 Antigen / Q000378:metabolism / Q000502:physiology; D060890:B7-H1 Antigen; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D020022:Genetic Predisposition to Disease; D008562:Membrane Glycoproteins / Q000378:metabolism / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000276:immunology*; D009336:Necrosis; D010455:Peptides / Q000378:metabolism / Q000502:physiology; D061026:Programmed Cell Death 1 Receptor; D014397:Tuberculosis, Pulmonary / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control
chemical_list: D000336:Aerosols; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D018984:Epitopes, T-Lymphocyte; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor