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

SummaryVaccinologists 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