Homotypic SLAMF1:SLAMF1 interactions between innate T cells and neutrophils activate fungal killing by neutrophils

Abstract

Neutrophils and monocytes are the main fungal effector cells in restricting Blastomyces dermatitidis (Bd) and other fungi at the respiratory mucosa. However, understanding how phagocytes become activated and recruited to the site of infection is still incompletely understood. Innate lymphocytes and myeloid cells have been found to communicate and play an essential part in activating neutrophils and other effector cells to kill fungi. Here, we identified that Signaling Lymphocytic Activation Molecule 1 (SLAMF1) is a key host immune receptor involved in orchestrating a cellular and molecular signaling network that leads to the activation of phagocytes. By using mice to conditionally eliminate SLAMF1 receptor expression on innate CD4+ or TCR{gamma}{delta}+ T cells, we uncovered that these innate lymphocytes augment neutrophil killing of Bd in a SLAMF1 dependent manner. SLAMF1 expression on neutrophils enabled homotypic SLAMF1:SLAMF1 interactions with innate CD4+ T cells, which prompted release of soluble factors that activated neutrophils to kill fungi. Our work furnishes new mechanistic insight about the role of SLAMF1 in mobilizing innate immune cells to induce phagocyte-driven killing of inhaled fungi. Author SummaryEmerging fungal diseases represent a significant and growing global public health threat fueled by increased anti-fungal resistance and rising number of immunocompromised individuals. Most fungal infections are respiratory and occur when inhaled fungal spores settle in the lungs and cause inflammation or tissue damage. The innate immune system is the first line of defense in the lungs but the mechanisms by which the host immune system becomes activated and mounts a protective response is still not completely understood. We identified a receptor on innate immune cells that facilitates communication between cells and recruits and activates killer cells that engulf and destroy the fungal pathogen. We uncovered that the receptor on the cell surface of innate immune cells mediates its function through cell contact and induction of soluble factors. Our work offers new mechanistic insight about how the innate immune system becomes activated by the presence of fungi and orchestrates an effective host response. We envision that soluble receptor could be harnessed for future anti-fungal therapy.