CD8 T cells drive anti-cancer immunity in response to antigen-presenting cells such as dendritic cells and subpopulations of monocytes and macrophages. While CD14 classical monocytes modulate CD8 T cell responses, the contributions of CD16 nonclassical monocytes to this process remain unclear. Herein we explored the role of nonclassical monocytes in CD8 T cell activation by utilizing E2-deficient (E2) mice that lack nonclassical monocytes.
View Article and Find Full Text PDFAnti-PD-1/PD-L1 immune checkpoint blockade (ICB) therapy has revolutionized the treatment of many types of cancer over the past decade. The initial therapeutic hypothesis underlying the mechanism of anti-PD-1/PD-L1 ICB was built around the premise that it acts locally in the tumor, reversing the exhaustion of PD-1CD8 T cells by "releasing the brakes." However, recent studies have provided unprecedented insight into the complexity within the CD8 T-cell pool in the tumor microenvironment (TME).
View Article and Find Full Text PDFEnhancer of Zeste Homolog 2 (EZH2) inhibitors (EZH2i) are approved to treat certain cancer types. Previous studies have suggested the potential to combine EZH2i with immune checkpoint blockade targeting coinhibitory receptors like PD-(L)1 and CTLA-4, but whether it can also enhance the activity of agents targeting costimulatory receptors is not known. Here, we explore the combination between EZH2i and an agonist antibody targeting the T cell costimulatory receptor 4-1BB (α4-1BB).
View Article and Find Full Text PDFA paradigm shift in the understanding of the exhausted CD8 T cell (T) lineage is underway. Originally thought to be a uniform population that progressively loses effector function in response to persistent antigen, single-cell analysis has now revealed that CD8 T is composed of multiple interconnected subpopulations. The heterogeneity within the CD8 T lineage is comprised of immune checkpoint blockade (ICB) permissive and refractory subsets termed stem-like and terminally differentiated cells, respectively.
View Article and Find Full Text PDFEnhancer of zeste 2 (EZH2) is the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) that mediates di- and trimethylation of histone 3 lysine 27 effectively precluding successful gene transcription at these loci. This class of epigenetic modifications facilitates the maintenance of tissue-specific cellular transcriptional programs as cells undergoing successive rounds of proliferation. CD8+ T cells are effective mediators of adaptive immunity and function to eliminate virus- and bacteria-infected cells as well as tumor cells.
View Article and Find Full Text PDFArterioscler Thromb Vasc Biol
January 2019
Objective- Three distinct human monocyte subsets have been identified based on the surface marker expression of CD14 and CD16. We hypothesized that monocytes were likely more heterogeneous in composition. Approach and Results- We used the high dimensionality of mass cytometry together with the FlowSOM clustering algorithm to accurately identify and define monocyte subsets in blood of healthy human subjects and those with coronary artery disease (CAD).
View Article and Find Full Text PDFObjective: Nonclassical monocytes (NCM) function to maintain vascular homeostasis by crawling or patrolling along the vessel wall. This subset of monocytes responds to viruses, tumor cells, and other pathogens to aid in protection of the host. In this study, we wished to determine how early atherogenesis impacts NCM patrolling in the vasculature.
View Article and Find Full Text PDFObjective: Human monocyte subsets are defined as classical (CD14CD16), intermediate (CD14CD16), and nonclassical (CD14CD16). Alterations in monocyte subset frequencies are associated with clinical outcomes, including cardiovascular disease, in which circulating intermediate monocytes independently predict cardiovascular events. However, delineating mechanisms of monocyte function is hampered by inconsistent results among studies.
View Article and Find Full Text PDFMononuclear phagocytes are a heterogeneous family that occupy all tissues and assume numerous roles to support tissue function and systemic homeostasis. Our ability to dissect the roles of individual subsets is limited by a lack of technologies that ablate gene function within specific mononuclear phagocyte sub-populations. Using Nr4a1-dependent Ly6C monocytes, we present a proof-of-principle approach that addresses these limitations.
View Article and Find Full Text PDFArterioscler Thromb Vasc Biol
September 2016
Monocytes and macrophages are key immune cells involved in the early progression of atherosclerosis. Transcription factors that control their development in the bone marrow are important therapeutic targets to control the numbers and functions of these cells in disease. This review highlights what is currently known about the transcription factors that are critical for monocyte development.
View Article and Find Full Text PDFThe molecular mechanisms that link the sympathetic stress response and inflammation remain obscure. Here we found that the transcription factor Nr4a1 regulated the production of norepinephrine (NE) in macrophages and thereby limited experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis. Lack of Nr4a1 in myeloid cells led to enhanced NE production, accelerated infiltration of leukocytes into the central nervous system (CNS) and disease exacerbation in vivo.
View Article and Find Full Text PDFThe immune system plays an important role in regulating tumor growth and metastasis. Classical monocytes promote tumorigenesis and cancer metastasis, but how nonclassical "patrolling" monocytes (PMo) interact with tumors is unknown. Here we show that PMo are enriched in the microvasculature of the lung and reduce tumor metastasis to lung in multiple mouse metastatic tumor models.
View Article and Find Full Text PDFThe transcription factor IFN regulatory factor (IRF)4 was shown to play a crucial role in the protective CD8(+) T cell response; however, regulation of IRF4 expression in CD8(+) T cells remains unclear. In this article, we report a critical role for Nr4a1 in regulating the expansion, differentiation, and function of CD8(+) T cells through direct transcriptional repression of Irf4. Without Nr4a1, the regulation of IRF4 is lost, driving an increase in Irf4 expression and, in turn, resulting in a faster rate of CD8 T cell proliferation and expansion.
View Article and Find Full Text PDFDendritic cells (DCs) direct CD4(+) T-cell differentiation into diverse helper (Th) subsets that are required for protection against varied infections. However, the mechanisms used by DCs to promote Th2 responses, which are important both for immunity to helminth infection and in allergic disease, are currently poorly understood. We demonstrate a key role for the protein methyl-CpG-binding domain-2 (Mbd2), which links DNA methylation to repressive chromatin structure, in regulating expression of a range of genes that are associated with optimal DC activation and function.
View Article and Find Full Text PDFThe archetypal Th2 cytokine IL-4 has previously been shown to alternatively activate murine macrophages and, more recently, dendritic cells (DCs) both in vitro and in vivo. IL-4 has also been shown to induce Aldh1a2 (aldehyde dehydrogenase 1a2) expression in murine macrophages recruited to the peritoneal cavity. However, the influence of IL-4 on DC Aldh1a2 induction in vivo has not yet been addressed.
View Article and Find Full Text PDFThe NR4A nuclear receptor family member Nr4a1 is strongly induced in thymocytes undergoing selection, and has been shown to control the development of Treg cells; however the role of Nr4a1 in CD8(+) T cells remains undefined. Here we report a novel role for Nr4a1 in regulating the development and frequency of CD8(+) T cells through direct transcriptional control of Runx3. We discovered that Nr4a1 recruits the corepressor, CoREST to suppress Runx3 expression in CD8(+) T cells.
View Article and Find Full Text PDFMacrophages (MΦs) colonize tissues during inflammation in two distinct ways: recruitment of monocyte precursors and proliferation of resident cells. We recently revealed a major role for IL-4 in the proliferative expansion of resident MΦs during a Th2-biased tissue nematode infection. We now show that proliferation of MΦs during intestinal as well as tissue nematode infection is restricted to sites of IL-4 production and requires MΦ-intrinsic IL-4R signaling.
View Article and Find Full Text PDFAlternatively activated macrophages (AAMϕ) are a major component of the response to helminth infection; however, their functions remain poorly defined. To better understand the helminth-induced AAMϕ phenotype, we performed a systems-level analysis of in vivo derived AAMϕ using an established mouse model. With next-generation RNA sequencing, we characterized the transcriptomes of peritoneal macrophages from BALB/c and IL4Rα(-/-) mice elicited by the nematode Brugia malayi, or via intraperitoneal thioglycollate injection.
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