Monocyte-derived galectin-1 promotes tissue-resident memory T cell response - Despite the availability of antiviral drugs and vaccines, the influenza virus causes widespread infection, leading to more than 35,000 deaths in the United States annually . After influenza infection, tissue -resident CD8+ memory T cells (TRMs) are generated in the respiratory tract and rapidly reactivated upon reinfection, providing immediate effector functions to limit viral replication and immunopathology. Therefore, the generation and maintenance of robust long-term memory CD8 T cells in the respiratory tract is an important strategy for effective vaccine design. Indeed, several intranasal influenza vaccines were developed to mimic a natural infection, which brings the advantage of eliciting tissue resident immunity to prevent or eliminate infection at the site of entry. However, unlike in the skin or intestine, TRM cells in the respiratory tract are relatively short-lived with increased apoptotic signatures. Thus, immunization of the respiratory tract with mucosal vaccination often results in inadequate protection. We undertook this study to address a key question regarding the nature of the tissue microenvironment that aids TRM establishment in the respiratory tract. Importantly, can we harness these tissue- specific cues to prolong TRM longevity at the tissue sites? In our unpublished preliminary studies, we tracked the fate of diverse myeloid cells in the lung after influenza infection and discovered that a subset of the newly recruited monocytes differentiates and persists in the mouse lung for more than 4 months after infection. Surprisingly, selective depletion of the novel monocyte subset significantly reduced TRM formation. This long- lasting monocyte subset produces a high level of galectin-1 (Gal-1), which directly activates CD2 expressed on CD8 T cells and enhances TRM-mediated sensing of TGF-β, a key cytokine that promotes virus-specific memory T cell differentiation and tissue persistence. Based on these findings, we propose the presence of a “monocyte- derived memory-like subset” that may prompt functional adaptations during influenza infections. We further hypothesize that the Gal-1/CD2/TGF-β axis is a major cell-intrinsic program through which tissue-resident myeloid cells guide long-lasting T cell memory formation in the respiratory tract. If the innate immune-mediated antiviral memory response persists at the site of antigen exposure, greater protection against viral infection may be achieved, thus offering a promising strategy for effective vaccine development. Indeed, we also showed that intranasal administration of recombinant Gal-1 as an adjuvant for a live-attenuated influenza vaccine induced superior TRM responses. We will (1) investigate monocyte differentiation during immune memory formation after influenza infection, (2) determine how Gal-1 produced by the novel monocyte subset regulates protective antiviral T cell immunity, and (3) test a novel nasal vaccine strategy using recombinant Gal-1. The results of these studies will provide a useful scientific basis for the design of vaccine strategies capable of establishing productive crosstalk between innate and adaptive immunity, leading to the induction of durable immunity, and may have a tangible impact on vaccine strategies against other respiratory viruses.
