Abstract Mucosa-associated invariant T (MAIT) cells are innate-like MR1-restricted T cells broadly distributed in human tissues. MAIT cells adapt their antigen-specific response patterns depending on cytokine cues such as IL-12 or IL-18 in the microenvironment, shifting toward either IL-10+ or IL-17+ profiles. However, if such patterns are maintained in the context of inflammatory diseases is unknown. Here, we investigated MAIT cell functional plasticity in Crohn’s disease (CD). Circulating MAIT cells in CD patients were impaired both in terms of numbers, and in terms of interferon γ (IFN-γ) and tumor necrosis factor (TNF) expression, and cytotoxic properties in response to MR1-presented antigen. However, the MAIT cell regulatory IL-10+ profile and the IL-17A+ profile were compromised only during active disease and relatively preserved during remission. Transcriptional analysis of intestinal T cells suggested that MAIT cells in CD displayed elevated GNLY and NKG7 expression, while transcripts associated with regulation and quiescence characterized MAIT cells in healthy donor control tissue. There were also distinct transcriptional signatures according to localization, where intra-epithelial MAIT cells exhibited a tissue resident regulatory profile, whereas those in the lamina propria showed signs of activation and recruitment. Finally, we assessed whether treatments for CD influenced MAIT cell functionality in vitro. Corticosteroids and upadacitinib inhibited MAIT cell activation, yet upadacitinib promoted increased GM-CSF and IL-17A expression in the context of combined antigen and IL-18 stimulation. These findings indicate that MAIT cell functional response patterns are influenced by CD disease stage, treatment, and tissue localization.
Abstract CD8+ tissue-resident memory T cells (TRM) in the upper respiratory tract (URT) limit viral replication after transmission and prevent spread to the lower respiratory tract (LRT), whereas LRT CD8+ TRM are important for limiting immunopathology in the lung and promoting efficient viral clearance. Although the presence of local respiratory antigen is thought to be required for CD8+ TRM development in the LRT but not the URT, the relationship between local antigen encounter and cytokine signaling that influences TRM differentiation in distinct niches of the respiratory tract remains unknown. Here, we show using murine models that while URT TRM generated in the presence or absence of local respiratory antigen are phenotypically, transcriptionally, and functionally similar throughout the respiratory tract, their developmental pathways are compartmentally distinct and characterized by a context-dependent compensatory relationship between antigen and cytokine signaling. In the absence of local antigen, URT CD8+ TRM formation required TGF-β signaling, and notably, while both IL-15 and IL-33 were broadly dispensable in the URT, IL-33 was able to rescue LRT CD8+ TRM development in the absence of local antigen. Together, these findings highlight key differences for CD8+ TRM development in distinct areas of the respiratory tract, offering valuable insights into the development of mucosal cellular immunity following intranasal and parenteral vaccination.
Abstract Eosinophils are pleiotropic cells and can respond to a wide array of inflammatory stimuli, including respiratory viral infection. Although they are historically associated with adverse outcomes in vaccinated hosts after breakthrough infection, such as during vaccine-associated enhanced respiratory disease (VAERD) for respiratory syncytial virus (RSV), eosinophils can also help mediate antiviral immunity. We previously observed mild, nonpathological lung eosinophilia in vaccinated mice experiencing influenza breakthrough infection, distinct from VAERD. Here, we investigated the factors driving this eosinophil recruitment and their contribution to host outcomes during influenza breakthrough infection. Vaccine-elicited Abs partially mediate eosinophil recruitment to the lungs during infection but do not confer full protection against viral replication or disease. Live viral replication was needed for robust eosinophil recruitment. Furthermore, both CD4 and CD8 T cells were required for optimal eosinophil accumulation in the lungs. Intramuscular vaccination resulted in the induction of a balanced type 1/2 response in the spleen and mainly a type 2 response in the lung upon infection, whereas a type 1 immune response dominated in the lungs of unvaccinated mice upon infection. Eosinophil depletion studies revealed strain-dependent effects: in BALB/c mice, eosinophil depletion did not significantly affect morbidity, viral load, lung inflammation, or lung lesion severity. However, in C57BL/6 mice, eosinophil depletion improved viral control and reduced pro-inflammatory cytokine expression. Our findings highlight the complex interplay among vaccine-induced immunity, eosinophil recruitment, and host genetic background in shaping outcomes during influenza breakthrough infection, with implications for vaccine strategies and immunopathology mitigation in diverse populations.
Abstract The lymphatic system is essential for the development of innate and adaptive immune responses to pathogens, including during viral infection and vaccination. Functioning as an integrated network composed of lymphatic vessels, lymphoid organs, and fluid, it serves as a central hub for viral entry, recognition, trafficking, replication, dissemination, and eventual clearance. While the lymphatic system’s role in shaping the host immune responses is well-established, its specific involvement in viral movement and infection is only beginning to emerge in detail. This review explores the lymphatic system’s contribution to antiviral defense, with emphasis on direct interactions with virions. We highlight mechanisms of viral recognition, the role of the lymphatic system in viral transport, and the known ways in which the lymphatic microenvironment shapes the quality and strength of adaptive immunity. Together, these perspectives frame the lymphatic system not as a passive transport network but as an active and underappreciated determinant of antiviral protection.
Abstract Epidemiologic studies suggest that patients with pre-existing type 1 diabetes have a decreased risk of developing melanoma, prostate cancer, and breast cancer, although the underlying mechanism remains unresolved. In translational model studies, we observed that a streptozotocin-induced high blood glucose model exhibited restricted melanoma and carcinoma (mammary, lung, and colon) growth in association with extended overall survival. Tumor-infiltrating CD8+ T cells were responsible for tumor growth restriction. Tumor-infiltrating CD8+ T cells but not tumor cells themselves exhibited higher glycolytic and cytotoxic activity in high-glucose hosts. Such improved antitumor T cell function was linked to upregulated expression of Igf1, Igf1R, and phospho-mTOR in CD8+ T cells in the tumor microenvironment. High blood glucose patient-derived peripheral CD8+ T cells displayed superior activation in vitro after allogenic tumor antigen stimulation versus nondiabetic CD8+ T cells. Activation of high-glucose-patient CD8+ T cells was sensitive to targeted antagonism of IGF1R and mTOR, supporting the operational involvement of the IGF1R-mTOR signaling axis. Our results suggest that selective activation of the intrinsic IGF1R-mTOR signaling axis in CD8+ T cells serves as a preferred endpoint to achieving more effective immunotherapy outcomes in cancer patients.
