title: Th1 Differentiation Drives the Accumulation of Intravascular, Non-protective CD4 T Cells during Tuberculosis.
abstract: Recent data indicate that the differentiation state of Th1 cells determines their protective capacity against tuberculosis. Therefore, we examined the role of Th1-polarizing factors in the generation of protective and non-protective subsets of Mtb-specific Th1 cells. We find that IL-12/23p40 promotes Th1 cell expansion and maturation beyond the CD73+CXCR3+T-betdimstage, and T-bet prevents deviation of Th1 cells into Th17 cells. Nevertheless, IL- 12/23p40 and T-bet are also essential for the production of a prominent subset of intravascular CX3CR1+KLRG1+Th1 cells that persists poorly and can neither migrate into the lung parenchyma nor control Mtb growth. Furthermore, T-bet suppresses development of CD69+CD103+tissue resident phenotype effectors in lung. In contrast, Th1-cell-derived IFN-γ inhibits the accumulation of intravascular CX3CR1+KLRG1+Th1 cells. Thus, although IL-12 and T-bet are essential host survival factors, they simultaneously oppose lung CD4 T cell responses at several levels, demonstrating the dual nature of Th1 polarization in tuberculosis.
authors.affiliation: T-Lymphocyte Biology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Sallin
authors.affiliation: T-Lymphocyte Biology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Sakai
authors.affiliation: T-Lymphocyte Biology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Keith D
authors.initials: KD
authors.lastname: Kauffman
authors.affiliation: Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.
authors.forename: Howard A
authors.initials: HA
authors.lastname: Young
authors.affiliation: Molecular and Cellular Immunoregulation Unit, Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Jinfang
authors.initials: J
authors.lastname: Zhu
authors.affiliation: T-Lymphocyte Biology Unit, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: barberd@niaid.nih.gov.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Barber
mesh_terms: D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology; D002454:Cell Differentiation; D002999:Clone Cells; D045142:Cross-Priming / Q000276:immunology; D054884:Host-Pathogen Interactions / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000378:metabolism; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000502:physiology; D020825:T-Box Domain Proteins; D018417:Th1 Cells / Q000166:cytology* / Q000276:immunology*; D014376:Tuberculosis / Q000276:immunology* / Q000382:microbiology / Q000473:pathology*; D000098815:T-bet Transcription Factor
chemical_list: D000942:Antigens, Bacterial; D053762:Interleukin-12 Subunit p40; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D018664:Interleukin-12; D007371:Interferon-gamma
keywords: IL-12; T cell migration; T-bet; Th1 cells; terminal effector; tuberculosis