Neutrophils are amongst the first cells to respond to inflammation and infection. Although they play a key role in limiting the dissemination of pathogens, the study of their dynamic behavior in ...immune organs remains elusive. In this work, we characterized
the dynamic behavior of neutrophils in the mouse popliteal lymph node (PLN) after influenza vaccination with UV-inactivated virus. To achieve this, we used an image-based systems biology approach to detect the motility patterns of neutrophils and to associate them to distinct actions. We described a prominent and rapid recruitment of neutrophils to the PLN following vaccination, which was dependent on the secretion of the chemokine CXCL1 and the alarmin molecule IL-1α. In addition, we observed that the initial recruitment occurred mainly via high endothelial venules located in the paracortical and interfollicular regions of the PLN. The analysis of the spatial-temporal patterns of neutrophil migration demonstrated that, in the initial stage, the majority of neutrophils displayed a patrolling behavior, followed by the formation of swarms in the subcapsular sinus of the PLN, which were associated with macrophages in this compartment. Finally, we observed using multiple imaging techniques, that neutrophils phagocytize and transport influenza virus particles. These processes might have important implications in the capacity of these cells to present viral antigens.
The mechanism by which inflammation influences the adaptive response to vaccines is not fully understood. Here, we examine the role of lymph node macrophages (LNMs) in the induction of the cytokine ...storm triggered by inactivated influenza virus vaccine. Following vaccination, LNMs undergo inflammasome-independent necrosis-like death that is reliant on MyD88 and Toll-like receptor 7 (TLR7) expression and releases pre-stored interleukin-1α (IL-1α). Furthermore, activated medullary macrophages produce interferon-β (IFN-β) that induces the autocrine secretion of IL-1α. We also found that macrophage depletion promotes lymph node-resident dendritic cell (LNDC) relocation and affects the capacity of CD11b+ LNDCs to capture virus and express co-stimulatory molecules. Inhibition of the IL-1α-induced inflammatory cascade reduced B cell responses, while co-administration of recombinant IL-1α increased the humoral response. Stimulation of the IL-1α inflammatory pathway might therefore represent a strategy to enhance antigen presentation by LNDCs and improve the humoral response against influenza vaccines.
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•Lymph node macrophages undergo necrosis after vaccination•Subcapsular sinus macrophage disappearance is mediated by TLR7•Macrophage death induces the activation and relocation of CD11b+ dendritic cells•IL-1α-mediated inflammation is essential for B cell responses
The mechanism by which inflammation influences the antibody response to vaccines is unclear. Chatziandreou et al. found that lymph node macrophages are key players in the initiation of the IL-1α-mediated inflammatory response that follows influenza vaccination.
The early phase of influenza infection occurs in the upper respiratory tract and the trachea, but little is known about the initial events of virus recognition and control of viral dissemination by ...the immune system. Here, we report that inflammatory dendritic cells (IDCs) are recruited to the trachea shortly after influenza infection through type I interferon-mediated production of the chemokine CCL2. We further show that recruited IDCs express the C-type lectin receptor SIGN-R1, which mediates direct recognition of the virus by interacting with N-linked glycans present in glycoproteins of the virion envelope. Activation of IDCs via SIGN-R1 triggers the production of the chemokines CCL5, CXCL9 and CXCL10, which initiate the recruitment of protective natural killer (NK) cells in the infected trachea. In the absence of SIGN-R1, the recruitment and activation of NK cells is impaired, leading to uncontrolled viral proliferation. In sum, our results provide insight into the orchestration of the early cellular and molecular events involved in immune protection against influenza.
Immunological memory is a hallmark of adaptive immunity that confers long-lasting protection from reinfections. Memory CD8
T cells provide protection by actively scanning for their cognate antigen ...and migrating into inflamed tissues. Trafficking patterns of CD8
T cells are also a major determinant of cell fate outcomes during differentiation into effector and memory cell states. CD8
T-cell trafficking must therefore be dynamically and tightly regulated to ensure that CD8
T cells arrive at the correct locations and differentiate to acquire appropriate effector functions. This review aims to discuss the importance of CD8
T-cell trafficking patterns in regulating effector and memory differentiation, maintenance, and reactivation.
A common metabolic alteration in the tumor microenvironment (TME) is lipid accumulation, a feature associated with immune dysfunction. Here, we examined how CD8+ tumor infiltrating lymphocytes (TILs) ...respond to lipids within the TME. We found elevated concentrations of several classes of lipids in the TME and accumulation of these in CD8+ TILs. Lipid accumulation was associated with increased expression of CD36, a scavenger receptor for oxidized lipids, on CD8+ TILs, which also correlated with progressive T cell dysfunction. Cd36−/− T cells retained effector functions in the TME, as compared to WT counterparts. Mechanistically, CD36 promoted uptake of oxidized low-density lipoproteins (OxLDL) into T cells, and this induced lipid peroxidation and downstream activation of p38 kinase. Inhibition of p38 restored effector T cell functions in vitro, and resolution of lipid peroxidation by overexpression of glutathione peroxidase 4 restored functionalities in CD8+ TILs in vivo. Thus, an oxidized lipid-CD36 axis promotes intratumoral CD8+ T cell dysfunction and serves as a therapeutic avenue for immunotherapies.
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•The tumor microenvironment is enriched with lipids and oxidized lipids•Dysfunctional CD8+ TILs increase CD36 expression and OxLDL uptake•OxLDL uptake via CD36 inhibits T cell effector functions through lipid peroxidation•GPX4 overexpression promotes CD8+ TIL functionality
Lipid accumulation is a common metabolic alteration in the tumor microenvironment. Xu et al. show that intratumoral CD8+ T cells adapt to increased lipid concentrations by increasing expression of the scavenger receptor CD36. This, in turn, leads to intracellular accumulation of oxidized lipid and T cell dysfunction downstream of lipid peroxidation.
CD8+ tissue-resident memory T cells (TRM cells) are poised at the portals of infection and provide long-term protective immunity. Despite their critical roles, the precise mechanics governing TRM ...cell reactivation in situ are unknown. Using a TCR-transgenic Nur77-GFP reporter to distinguish "antigen-specific" from "bystander" reactivation, we demonstrate that lung CD8+ TRM cells are reactivated more quickly, yet less efficiently, than their counterparts in the draining LNs (TLN cells). Global profiling of reactivated memory T cells revealed tissue-defined and temporally regulated recall response programs. Unlike the reactivation of CD8+ TLN cells, which is strictly dependent on CD11c+XCR1+ APCs, numerous antigen-presenting partners, both hematopoietic and non-hematopoietic, were sufficient to reactivate lung CD8+ TRM cells, but the quality of TRM cell functional responses depended on the identity of the APCs. Together, this work uncovers fundamental differences in the activation kinetics, mechanics, and effector responses between CD8+ memory T cells in peripheral vs. lymphoid organs, revealing a novel tissue-specific paradigm for the reactivation of memory CD8+ T cells.
The innate immune response generated against influenza infection is critical for the inhibition of viral dissemination. The trachea contains different types of innate immune cells that protect the ...respiratory tract from pathogen invasion. Among them, γδ T cells have the ability to rapidly generate large amounts of pro‐inflammatory cytokines to preserve mucosal barrier homeostasis during infection. However, little is known about their role during the early phase of influenza infection in the airways. In this study, we found that, early after infection, γδ T cells are recruited and activated in the trachea and outnumber αβ T cells during the course of the influenza infection that follows. We also showed that the majority of the recruited γδ T cells express the Vγ4 TCR chain and infiltrate in a process that involves the chemokine receptor CXCR3. In addition, we demonstrated that γδ T cells promote the recruitment of protective neutrophils and NK cells to the tracheal mucosa. Altogether, our results highlight the importance of the immune responses mediated by γδ T cells.
Innate recognition of influenza virus infection is critical for the control of the viral dissemination. Among the innate immune cells recruited to the infected trachea, Vγ4 + γδ T cells rapidly secrete IL‐17A that contributes to neutrophil recruitment and the elimination of virus‐infected cells from the trachea.
Immunological memory is a hallmark of adaptive immunity that confers long-lasting protection from reinfections. Memory CD8+ T cells provide protection by actively scanning for their cognate antigen ...and migrating into inflamed tissues. Trafficking patterns of CD8+ T cells are also a major determinant of cell fate outcomes during differentiation into effector and memory cell states. CD8+ T-cell trafficking must therefore be dynamically and tightly regulated to ensure that CD8+ T cells arrive at the correct locations and differentiate to acquire appropriate effector functions. This review aims to discuss the importance of CD8+ T-cell trafficking patterns in regulating effector and memory differentiation, maintenance, and reactivation.
The limited efficacy of immunotherapies against glioblastoma underscores the urgency of better understanding immunity in the central nervous system. We found that treatment with αCTLA-4, but not ...αPD-1, prolonged survival in a mouse model of mesenchymal-like glioblastoma. This effect was lost upon the depletion of CD4+ T cells but not CD8+ T cells. αCTLA-4 treatment increased frequencies of intratumoral IFNγ-producing CD4+ T cells, and IFNγ blockade negated the therapeutic impact of αCTLA-4. The anti-tumor activity of CD4+ T cells did not require tumor-intrinsic MHC-II expression but rather required conventional dendritic cells as well as MHC-II expression on microglia. CD4+ T cells interacted directly with microglia, promoting IFNγ-dependent microglia activation and phagocytosis via the AXL/MER tyrosine kinase receptors, which were necessary for tumor suppression. Thus, αCTLA-4 blockade in mesenchymal-like glioblastoma promotes a CD4+ T cell-microglia circuit wherein IFNγ triggers microglia activation and phagocytosis and microglia in turn act as antigen-presenting cells fueling the CD4+ T cell response.
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•αCTLA-4 therapy induces protective CD4+ Th1 cells against mesenchymal glioblastomas•Th1-derived IFNγ induces MHC-II+ microglia that sustains Th1 anti-glioma immunity•Th1 cells promote microglia phagocytosis of gliomas via AXL-MER receptor signaling•Microglia and MHC-II expression are protective correlates in human glioblastoma
Immunotherapies against glioblastoma exhibit limited efficacy. Chen et al. examine the impact of immunotherapy in mesenchymal glioblastomas and find that αCTLA-4 treatment promotes tumor suppression in a manner dependent on CD4+ T cells. Mechanistically, microglia serve as essential MHC-II antigen-presenting cells that sustain anti-tumor IFNγ+ CD4+ T cells, which in turn stimulate microglial phagocytic function via AXL-MER signaling.
Although tumor growth requires the mitochondrial electron transport chain (ETC), the relative contribution of complex I (CI) and complex II (CII), the gatekeepers for initiating electron flow, ...remains unclear. In this work, we report that the loss of CII, but not that of CI, reduces melanoma tumor growth by increasing antigen presentation and T cell-mediated killing. This is driven by succinate-mediated transcriptional and epigenetic activation of major histocompatibility complex-antigen processing and presentation (MHC-APP) genes independent of interferon signaling. Furthermore, knockout of methylation-controlled J protein (MCJ), to promote electron entry preferentially through CI, provides proof of concept of ETC rewiring to achieve antitumor responses without side effects associated with an overall reduction in mitochondrial respiration in noncancer cells. Our results may hold therapeutic potential for tumors that have reduced MHC-APP expression, a common mechanism of cancer immunoevasion.
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