The immune system plays an important role in regulating tumor growth and metastasis. For example, classical monocytes promote tumorigenesis and cancer metastasis; however, how nonclassical “patrolling” monocytes interact with tumors is unknown. Here we show that patrolling monocytes are enriched in the microvasculature of the lung and reduce tumor metastasis to lung in multiple mouse metastatic tumor models. Nr4a1-deficient mice, which specifically lack patrolling monocytes, showed increased lung metastasis in vivo. Transfer of Nr4a1-proficient patrolling monocytes into Nr4a1-deficient mice prevented tumor invasion in lung. Patrolling monocytes established early interactions with metastasizing tumor cells, scavenged tumor material from the lung vasculature and promoted natural killer cell recruitment and activation. Thus, patrolling monocytes contribute to cancer immunosurveillance and may be targets for cancer immunotherapy.
Atherosclerosis is a chronic inflammatory disease of large and medium-sized arteries characterized by leukocyte accumulation in the vessel wall. Both innate and adaptive immune responses contribute to atherogenesis, but the identity of atherosclerosis-relevant antigens and the role of antigen presentation in this disease remain poorly characterized. We developed live-cell imaging of explanted aortas to compare the behavior and role of APCs in normal and atherosclerotic mice. We found that CD4 + T cells were capable of interacting with fluorescently labeled (CD11c-YFP + ) APCs in the aortic wall in the presence, but not the absence, of cognate antigen. In atherosclerosis-prone Apoe -/-CD11c-YFP + mice, APCs extensively interacted with CD4 + T cells in the aorta, leading to cell activation and proliferation as well as secretion of IFN-γ and TNF-α. These cytokines enhanced uptake of oxidized and minimally modified LDL by macrophages. We conclude that antigen presentation by APCs to CD4 + T cells in the arterial wall causes local T cell activation and production of proinflammatory cytokines, which promote atherosclerosis by maintaining chronic inflammation and inducing foam cell formation.
Recent work has demonstrated that following the clearance of infection a stable population of memory T cells remains present in peripheral organs and contributes to the control of secondary infections. However, little is known about how tissue-resident memory T cells behave in situ and how they encounter newly infected target cells. Here we demonstrate that antigen-specific CD8 + T cells that remain in skin following herpes simplex virus infection show a steady-state crawling behavior in between keratinocytes. Spatially explicit simulations of the migration of these tissue-resident memory T cells indicate that the migratory dendritic behavior of these cells allows the detection of antigen-expressing target cells in physiologically relevant time frames of minutes to hours. Furthermore, we provide direct evidence for the identification of rare antigen-expressing epithelial cells by skin-patrolling memory T cells in vivo. These data demonstrate the existence of skin patrol by memory T cells and reveal the value of this patrol in the rapid detection of renewed infections at a previously infected site.Cellular Potts Model | intravital imaging | HSV-1
The surveillance of body barriers relies on resident T cells whose repertoires are biased toward particular γδ T cell receptor lineages according to location. These γδ TCRs were shown to recognize stress-emergent ligands. Using intravital dynamics-immunosignal correlative microscopy, we report that epidermal T cell-expressed Vγ5 TCRs were constitutively clustered and functionally activated in vivo at steady-state, forming bona-fide immunological synapses that polarized and anchored T cell projections at squamous keratinocyte tight junctions. This synaptogenesis depended on TCR variable domains, Lck and αE(CD103)β7-integrin, but not the γδ lineage or NKG2D. In response to tissue stress, TCR-proximal signals did not increase significantly but underwent stress mode-dependent re-localization. Thus, the γδ TCR orchestrates barrier surveillance pro-actively, presumably by recognizing steady-state-expressed tissue ligands.
Molecular mechanisms linking the sympathetic stress response and inflammation remain enigmatic. Here we demonstrate that the transcription factor Nr4a1 regulates production of norepinephrine (NE) in macrophages, thereby limiting experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Lack of Nr4a1 in myeloid cells led to enhanced NE production, accelerated leukocyte infiltration to the central nervous system (CNS) and disease exacerbation in vivo. In contrast, myeloid-specific deletion of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis, protected against EAE. Further, we found that Nr4a1 repressed autocrine NE production in macrophages by recruiting the corepressor CoREST to the Th promoter. Our data reveal a new role for macrophages in neuroinflammation and identify Nr4a1 as a key regulator of macrophage catecholamine production.
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