title: Fungi subvert vaccine T cell priming at the respiratory mucosa by preventing chemokine-induced influx of inflammatory monocytes.
abstract: Vaccinologists strive to harness immunity at mucosal sites of pathogen entry. We studied respiratory delivery of an attenuated vaccine against Blastomyces dermatitidis. We created a T cell receptor transgenic mouse responsive to vaccine yeast and found that mucosal vaccination led to poor T cell activation in the draining nodes and differentiation in the lung. Mucosal vaccination subverted lung T cell priming by inducing matrix metalloproteinase 2 (MMP2), which impaired the action of the chemokine CCL7 on egress of CCR2(+) Ly6C(hi) inflammatory monocytes from the bone marrow and their recruitment to the lung. Studies in Mmp2(-/-) mice, or treatment with MMP inhibitor or rCCL7, restored recruitment of Ly6C(hi) monocytes to the lung and CD4(+) T cell priming. Mucosal vaccination against fungi and perhaps other respiratory pathogens may require manipulation of host MMPs in order to alter chemokine signals needed to recruit Ly6C(hi) monocytes and prime T cells at the respiratory mucosa.
authors.affiliation: Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792, USA. mwuethri@wisc.edu
authors.forename: Marcel
authors.initials: M
authors.lastname: Wüthrich
authors.forename: Karen
authors.initials: K
authors.lastname: Ersland
authors.forename: Thomas
authors.initials: T
authors.lastname: Sullivan
authors.forename: Kevin
authors.initials: K
authors.lastname: Galles
authors.forename: Bruce S
authors.initials: BS
authors.lastname: Klein
mesh_terms: D000818:Animals; D000950:Antigens, Ly / Q000276:immunology; D001758:Blastomyces / Q000276:immunology*; D001854:Bone Marrow Cells / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D002465:Cell Movement; D054410:Chemokine CCL7 / Q000037:antagonists & inhibitors / Q000378:metabolism; D005657:Fungal Vaccines / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D008213:Lymphocyte Activation; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008822:Mice, Transgenic; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D020545:Respiratory Mucosa / Q000276:immunology* / Q000382:microbiology; D014611:Vaccination
chemical_list: D000950:Antigens, Ly; C515451:Ccl7 protein, mouse; D054410:Chemokine CCL7; D005657:Fungal Vaccines; C494192:Ly-6C antigen, mouse; D061965:Matrix Metalloproteinase Inhibitors; D020778:Matrix Metalloproteinase 2