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Natural killer (NK) cells are vital components of the antiviral immune response, but their contributions in defense against influenza A virus (IAV) are not well understood. To better understand NK cell responses during IAV infections, we examined the magnitude, kinetics, and contribution of NK cells to immunity and protection during high- and low-dose IAV infections. Herein, we demonstrate an increased accumulation of NK cells in the lung in high-dose vs. low-dose infections. In part, this increase is due to the local proliferation of pulmonary NK cells. However, the majority of NK cell accumulation within the lungs and airways during an IAV infection is due to recruitment that is partially dependent upon CXCR3 and CCR5, respectively. Therefore, altogether, our results demonstrate that NK cells are actively recruited to the lungs and airways during IAV infection and that the magnitude of the recruitment may relate to the inflammatory environment found within the tissues during high- and low-dose IAV infections.

Influenza A virus (IAV) is a leading cause of respiratory infections, with increased risk of severe illness and death in the very young, aged, and immunocompromised individuals. In both mice and humans, IAV-specific T cell responses are protective during primary as well as homologous and heterologous challenge infections. Many mouse studies have focused on CD4 T cells specific for a single, known model or IAV antigen. However, studies have demonstrated that the IAV-specific CD4 T cell response comprises many epitopes spread across multiple viral proteins. Therefore, herein we track the antigen-experienced CD4 T cell response using the surrogate markers CD49d and CD11a. This novel surrogate marker method allows us to characterize the full IAV-specific CD4 T cell response without the potential bias that could occur when examining an individual Ag-specificity. Our findings demonstrate that the immunodominant I-A -binding NP epitope often used in studies of IAV-specific CD4 T cells represents only about 5% of the total IAV-specific CD4 T cell response. Further, we find that the kinetics of the full pulmonary CD4 T cell response is similar to that of NP -specific T cells and that the full CD4 T cell response in the lungs is predominantly composed of cells expressing the Th1 transcription factor T-bet, with smaller but significant portions of the response expressing the Treg and Tfh associated transcription factors Foxp3 and Bcl-6, respectively. Interestingly, although Th1 cells are the most abundant Th subset in the lungs of both BALB/c and C57Bl/6 mice following IAV, the relative abundance of Treg and Tfh is reversed in the different mouse strains. In BALB/c mice, Foxp3 cells are more abundant than Bcl6 cells, whereas in C57Bl/6 mice, there are more Bcl6 cells. As a whole, these data highlight the diversity of the endogenous CD4 T cell response to a primary IAV infection, providing an important context for past and future studies of the IAV-specific CD4 T cell response.

Glycerol monolaurate (GML) is a naturally occurring antimicrobial agent used commercially in numerous products and food items. GML is also used as a homeopathic agent and is being clinically tested to treat several human diseases. In addition to its anti-microbial function, GML suppresses immune cell proliferation and inhibits primary human T cell activation. GML suppresses T cell activation by altering membrane dynamics and disrupting the formation of protein clusters necessary for intracellular signaling. The ability of GML to disrupt cellular membranes suggests it may alter other cell types. To explore this possibility, we tested how GML affects human B cells. We found that GML inhibits BCR-induced cytokine production, phosphorylation of signaling proteins, and protein clustering, while also changing cellular membrane dynamics and dysregulating cytoskeleton rearrangement. Although similar, there are also differences between how B cells and T cells respond to GML. These differences suggest that unique intrinsic features of a cell may result in differential responses to GML treatment. Overall, this study expands our understanding of how GML impacts the adaptive immune response and contributes to a broader knowledge of immune modulating monoglycerides.

Pharmacological ascorbate (i.e., intravenous infusions of vitamin C reaching ~ 20 mM in plasma) is under active investigation as an adjuvant to standard of care anti-cancer treatments due to its dual redox roles as an antioxidant in normal tissues and as a prooxidant in malignant tissues. Immune checkpoint inhibitors (ICIs) are highly promising therapies for many cancer patients but face several challenges including low response rates, primary or acquired resistance, and toxicity. Ascorbate modulates both innate and adaptive immune functions and plays a key role in maintaining the balance between pro and anti-inflammatory states. Furthermore, the success of pharmacological ascorbate as a radiosensitizer and a chemosensitizer in pre-clinical studies and early phase clinical trials suggests that it may also enhance the efficacy and expand the benefits of ICIs.

Introduction Aromatase inhibitor (AI) therapy reduces breast cancer recurrence risk. However, some patients stop treatment early because of AI‐associated musculoskeletal symptoms (AIMSS). AIMSS is due in part to systemic inflammation. Cannabidiol (CBD) has anti‐nociceptive and anti‐inflammatory properties, making it a potential treatment option for AIMSS. Methods Women with stage 0–3 hormone receptor‐positive breast cancer experiencing AIMSS enrolled in this phase 2 clinical trial. Patients received CBD (Epidiolex), titrated over 4 weeks to 100 mg BID, for a total of 15 weeks. Patient‐reported outcomes were collected serially. The primary endpoint was the number of patients with at least a 2‐point reduction in worst pain from baseline to 15 weeks. Statistical analysis was completed using paired t‐tests and linear mixed models. Results Of 39 eligible patients, 28 completed protocol‐directed study treatment. Eleven discontinued treatment due to toxicity (n = 5) or per patient preference (n = 6). Seventeen of 39 patients met the primary endpoint (43.6%, 95% CI [28%, 60%]). Worst pain improved 0.13 per week of treatment (p < 0.001) for all patients; average improvement in worst pain was 1.95 points at the end of 15 weeks. Of the 28 patients who completed the study, average reduction in worst pain was 2.36 points (95% CI [−3.22, −1.49]) between baseline and Week 15. Conclusion Treatment with CBD was safe, tolerable, and associated with improvement in joint pain for a subset of patients. Additional studies are needed to further understand the impact of CBD on AIMSS and which patients are most likely to benefit from CBD treatment. Trial Registration www.clinicaltrials.gov: NCT04754399

Macrophages are critical in the pathogenesis of a diverse group of viral pathogens, both as targets of infection and for eliciting primary defense mechanisms. Our prior in vitro work identified that CD40 signaling in murine peritoneal macrophages protects against several RNA viruses by eliciting IL-12, which stimulates the production of interferon gamma (IFN-γ). Here, we examine the role of CD40 signaling in vivo. We show that CD40 signaling is a critical, but currently poorly appreciated, component of the innate immune response using two distinct infectious agents: mouse-adapted influenza A virus (IAV, PR8) and recombinant VSV encoding the Ebola virus glycoprotein (rVSV-EBOV GP). We find that stimulation of CD40 signaling decreases early IAV titers, whereas loss of CD40 elevated early titers and compromised lung function by day 3 of infection. Protection conferred by CD40 signaling against IAV is dependent on IFN-γ production, consistent with our in vitro studies. Using rVSV-EBOV GP that serves as a low-biocontainment model of filovirus infection, we demonstrate that macrophages are a CD40-expressing population critical for protection within the peritoneum and T-cells are the key source of CD40L (CD154). These experiments reveal the in vivo mechanisms by which CD40 signaling in macrophages regulates the early host responses to RNA virus infection and highlight how CD40 agonists currently under investigation for clinical use may function as a novel class of broad antiviral treatments.

Influenza A virus (IAV) causes significant morbidity and mortality worldwide due to seasonal epidemics and periodic pandemics. The antigenic drift/shift of IAV continually gives rise to new strains and subtypes, aiding IAV in circumventing previously established immunity. As a result, there has been substantial interest in developing a broadly protective IAV vaccine that induces, durable immunity against multiple IAVs. Previously, a polyanhydride nanoparticle-based vaccine or nanovaccine (IAV-nanovax) encapsulating H1N1 IAV antigens was reported, which induced pulmonary B and T cell immunity and resulted in cross-strain protection against IAV. A key feature of IAV-nanovax is its ability to easily incorporate diverse proteins/payloads, potentially increasing its ability to provide broad protection against IAV and/or other pathogens. Due to human susceptibility to both H1N1 and H3N2 IAV, several H3N2 nanovaccines were formulated herein with multiple IAV antigens to examine the \"plug-and-play\" nature of the polyanhydride nanovaccine platform and determine their ability to induce humoral and cellular immunity and broad-based protection similar to IAV-nanovax. The H3N2-based IAV nanovaccine formulations induced systemic and mucosal B cell responses which were associated with antigen-specific antibodies. Additionally, systemic and lung-tissue resident CD4 and CD8 T cell responses were enhanced post-vaccination. These immune responses corresponded with protection against both homologous and heterosubtypic IAV infection. Overall, these results demonstrate the plug-and-play nature of the polyanhydride nanovaccine platform and its ability to generate immunity and protection against IAV utilizing diverse antigenic payloads.

Influenza A virus (IAV)-specific T cell responses are important correlates of protection during primary and subsequent infections. Generation and maintenance of robust IAV-specific T cell responses relies on T cell interactions with dendritic cells (DCs). In this study, we explore the role of nucleotide-binding domain leucine-rich repeat containing receptor family member NLRC4 in modulating the DC phenotype during IAV infection. Nlrc4-/- mice had worsened survival and increased viral titers during infection, normal innate immune cell recruitment and IAV-specific CD8 T cell responses, but severely blunted IAV-specific CD4 T cell responses compared to wild-type mice. The defect in the pulmonary IAV-specific CD4 T cell response was not a result of defective priming or migration of these cells in Nlrc4-/- mice but was instead due to an increase in FasL+ DCs, resulting in IAV-specific CD4 T cell death. Together, our data support a novel role for NLRC4 in regulating the phenotype of lung DCs during a respiratory viral infection, and thereby influencing the magnitude of protective T cell responses.

Influenza A virus-specific (IAV-specific) T cell responses are important correlates of protection during primary and subsequent infections. The generation and maintenance of robust IAV-specific T cell responses relies on T cell interactions with dendritic cells (DCs). In this study, we explore the role of the nucleotide-binding domain leucine-rich repeat- containing receptor family member NLRC4 in modulating the DC phenotype during IAV infection. [Nlrc4.sup.-/-] mice had worsened survival and increased viral titers during infection, normal innate immune cell recruitment, and IAV-specific [CD8.sup.+] T cell responses, but severely blunted IAV-specific [CD4.sup.+] T cell responses compared with WT mice. The defect in the pulmonary IAV-specific [CD4.sup.+] T cell response was not a result of defective priming or migration of these cells in [Nlrc4.sup.-/-] mice but was instead due to an increase in [FasL.sup.+] DCs, resulting in IAV- specific [CD4.sup.+] T cell death. Together, our data support a role for NLRC4 in regulating the phenotype of lung DCs during a respiratory viral infection and thereby influencing the magnitude of protective T cell responses.

Resident synovial macrophages (RSM) provide immune sequestration of the joint space and are likely involved in initiation and perpetuation of the joint-specific immune response. We sought to identify RSM in synovial fluid (SF) and demonstrate migratory ability, in additional to functional changes that may perpetuate a chronic inflammatory response within joint spaces. We recruited human patients presenting with undifferentiated arthritis in multiple clinical settings. We used flow cytometry to identify mononuclear cells in peripheral blood and SF. We used a novel transwell migration assay with human synovium obtained intra-operatively to validate flow cytometry findings. We used single cell RNA-sequencing (scRNA-seq) to further identify macrophage/monocyte subsets. ELISA was used to evaluate the bone-resorption potential of SF. We were able to identify a rare population of CD14 , OPG , ZO-1 cells consistent with RSM in SF via flow cytometry. These cells were relatively enriched in the SF during infectious processes, but absolutely decreased compared to healthy controls. Similar putative RSM were identified using migration assays when MCP-1 and LPS were used as migratory stimulus. scRNA-seq revealed a population consistent with RSM transcriptionally related to CD56 cytotoxic dendritic cells and IDO M2 macrophages. We identified a rare cell population consistent with RSM, indicating these cells are likely migratory and able to initiate or coordinate both acute (septic) or chronic (autoimmune or inflammatory) arthritis. RSM analysis via scRNA-seq indicated these cells are M2 skewed, capable of antigen presentation, and have consistent functions in both septic and inflammatory arthritis.