title: Systemic Expression of Notch Ligand Delta-Like 4 during Mycobacterial Infection Alters the T Cell Immune Response.
abstract: The Notch ligand delta-like 4 (DLL4) is known to fine-tune the CD4+T cell cytokine response. DLL4 is expressed on the surface of antigen-presenting cells (APCs) in a MyD88-dependent manner. We found that DLL4 expression was upregulated on bone marrow progenitor cells and APCs in mice infected with BCGMycobacterium. Transfer of DLL4+progenitor cells from infected hosts resulted in an increase DLL4+myeloid cells in the spleen, indicating that expression of thedll4gene is propagated throughout hematopoiesis. We also found an increase in DLL4+monocytes from individuals who were infected withMycobacterium tuberculosis. In latent individuals, DLL4 expression correlated with increased cytokine production from T cells in response to PPD stimulation. Finally, antibody blockade of DLL4 reduced T cell cytokine production from naïve T cells stimulated with antigen. These results demonstrate that the Notch ligand DLL4 can influence T cell cytokine production in both humans and mice, and further reveal that expression of DLL4 is upregulated on early hematopoietic progenitors in response to chronic mycobacterial infection. These data suggest that widespread DLL4 expression may occur as a result of mycobacterial infection, and that this expression may alter CD4+T cell responses to both previously encountered and novel antigens.
authors.affiliation: Department of Pathology, University of Michigan Medical School , Ann Arbor, MI , USA.
authors.forename: Matthew A
authors.initials: MA
authors.lastname: Schaller
authors.affiliation: Department of Pathology, University of Michigan Medical School , Ann Arbor, MI , USA.
authors.forename: Ronald M
authors.initials: RM
authors.lastname: Allen
authors.affiliation: Department of Microbiology and Infectious Diseases, Toho University School of Medicine , Tokyo , Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Kimura
authors.affiliation: Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA, USA; Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA, USA; South African Tuberculosis Vaccine Initiative (SATVI), Institute of Infectious Diseases and Molecular Medicine, School of Child and Adolescent Health, University of Cape Town, Observatory, South Africa.
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Day
authors.affiliation: Department of Pathology, University of Michigan Medical School , Ann Arbor, MI , USA.
authors.forename: Steven L
authors.initials: SL
authors.lastname: Kunkel
keywords: Notch; hematopoiesis; monocytes; tuberculosis