Fungi Subvert Vaccine T Cell Priming at the Respiratory Mucosa by Preventing Chemokine-Induced Influx of Inflammatory Monocytes

• Published in: Immunity (Cambridge, Mass.) Vol. 36; no. 4; pp. 680 - 692
• Main Authors: Wüthrich, Marcel, Ersland, Karen, Sullivan, Thomas, Galles, Kevin, Klein, Bruce S.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20-04-2012; Elsevier Limited
• Subjects: Animals; Antigens, Ly - immunology; Blastomyces - immunology; Blastomyces dermatitidis; Bone marrow; Bone Marrow Cells - metabolism; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Cell activation; Cell Differentiation; Cell Line; Cell Movement; Chemokine CCL7 - antagonists & inhibitors; Chemokine CCL7 - metabolism; Chemokines; Chromium; Colleges & universities; Differentiation; Flow cytometry; Fungal infections; Fungal Vaccines - immunology; Fungi; Gelatinase A; Inflammation; Inflammation - immunology; Influenza; Lung; Lymphocyte Activation; Lymphocytes T; Matrix metalloproteinase; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase Inhibitors; Mice; Mice, Transgenic; Monocytes; Monocytes - immunology; Monocytes - metabolism; Mucosa; Mucosal immunity; Nodes; Pathogens; Respiratory Mucosa - immunology; Respiratory Mucosa - microbiology; T-cell receptor; Transgenic mice; Tuberculosis; Vaccination; Vaccines
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2012.02.015

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+ Ly6Chi 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 Ly6Chi 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 Ly6Chi monocytes and prime T cells at the respiratory mucosa.
► Fungi induce host matrix metalloproteinases at the respiratory mucosa ► Matrix metalloproteinases convert agonistic chemokines into antagonists ► Antagonistic cytokines prevent the influx of inflammatory monocytes to the lung ► Mucosal vaccination with some fungi fails to prime T cells in the lung