Chemokines and Chemokine Receptors: Positioning Cells for Host Defense and Immunity
TL;DR: This review focuses on recent advances in understanding how the chemokine system orchestrates immune cell migration and positioning at the organismic level in homeostasis, in acute inflammation, and during the generation and regulation of adoptive primary and secondary immune responses in the lymphoid system and peripheral nonlymphoid tissue.
Abstract: Chemokines are chemotactic cytokines that control the migratory patterns and positioning of all immune cells. Although chemokines were initially appreciated as important mediators of acute inflammation, we now know that this complex system of approximately 50 endogenous chemokine ligands and 20 G protein–coupled seven-transmembrane signaling receptors is also critical for the generation of primary and secondary adaptive cellular and humoral immune responses. Recent studies demonstrate important roles for the chemokine system in the priming of naive T cells, in cell fate decisions such as effector and memory cell differentiation, and in regulatory T cell function. In this review, we focus on recent advances in understanding how the chemokine system orchestrates immune cell migration and positioning at the organismic level in homeostasis, in acute inflammation, and during the generation and regulation of adoptive primary and secondary immune responses in the lymphoid system and peripheral nonlymphoid tissue.
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TL;DR: This Review focuses on the main chemokines that are found in the human tumour microenvironment, and elaborate on their patterns of expression, their regulation and their roles in immune cell recruitment and in cancer and stromal cell biology.
Abstract: The tumour microenvironment is the primary location in which tumour cells and the host immune system interact. Different immune cell subsets are recruited into the tumour microenvironment via interactions between chemokines and chemokine receptors, and these populations have distinct effects on tumour progression and therapeutic outcomes. In this Review, we focus on the main chemokines that are found in the human tumour microenvironment; we elaborate on their patterns of expression, their regulation and their roles in immune cell recruitment and in cancer and stromal cell biology, and we consider how they affect cancer immunity and tumorigenesis. We also discuss the potential of targeting chemokine networks, in combination with other immunotherapies, for the treatment of cancer.
1,271 citations
TL;DR: The results reveal distinct host inflammatory cytokine profiles to SARS-CoV-2 infection in patients, and highlight the association between COVID-19 pathogenesis and excessive cytokine release such as CCL2/MCP-1, CXCL10/IP-10, CCL3/MIP-1A, and CCL4/Mip1B.
Abstract: Circulating in China and 158 other countries and areas, the ongoing COVID-19 outbreak has caused devastating mortality and posed a great threat to public health. However, efforts to identify effectively supportive therapeutic drugs and treatments has been hampered by our limited understanding of host immune response for this fatal disease. To characterize the transcriptional signatures of host inflammatory response to SARS-CoV-2 (HCoV-19) infection, we carried out transcriptome sequencing of the RNAs isolated from the bronchoalveolar lavage fluid (BALF) and peripheral blood mononuclear cells (PBMC) specimens of COVID-19 patients. Our results reveal distinct host inflammatory cytokine profiles to SARS-CoV-2 infection in patients, and highlight the association between COVID-19 pathogenesis and excessive cytokine release such as CCL2/MCP-1, CXCL10/IP-10, CCL3/MIP-1A, and CCL4/MIP1B. Furthermore, SARS-CoV-2 induced activation of apoptosis and P53 signalling pathway in lymphocytes may be the cause of patients' lymphopenia. The transcriptome dataset of COVID-19 patients would be a valuable resource for clinical guidance on anti-inflammatory medication and understanding the molecular mechansims of host response.
918 citations
Cites background from "Chemokines and Chemokine Receptors:..."
...It has been shown that CCR2 and CCR5 deficient mice infected with mouse-adapted SARS-CoV virus exhibited defects in directing inflammatory cell to the airway, causing severe disease and increased mortality [38] ....
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TL;DR: The emerging evidence suggesting that the adrenergic signalling pathways associated with thermogenesis shape immune cell function is discussed, as well as the unexpected multiplicity of roles of the pyrogenic cytokine interleukin-6 (IL-6), both during fever induction and during the mobilization of lymphocytes to the lymphoid organs that are the staging ground for immune defence.
Abstract: Fever is a cardinal response to infection that has been conserved in warm-blooded and cold-blooded vertebrates for more than 600 million years of evolution. The fever response is executed by integrated physiological and neuronal circuitry and confers a survival benefit during infection. In this Review, we discuss our current understanding of how the inflammatory cues delivered by the thermal element of fever stimulate innate and adaptive immune responses. We further highlight the unexpected multiplicity of roles of the pyrogenic cytokine interleukin-6 (IL-6), both during fever induction and during the mobilization of lymphocytes to the lymphoid organs that are the staging ground for immune defence. We also discuss the emerging evidence suggesting that the adrenergic signalling pathways associated with thermogenesis shape immune cell function.
743 citations
TL;DR: In this paper, the authors used mass cytometry with extensive antibody panels to perform in-depth immune profiling of samples from 73 clear cell renal cell carcinoma (ccRCC) patients and five healthy controls.
683 citations
Cites background from "Chemokines and Chemokine Receptors:..."
...The M-5 population also exhibited direct immunosuppressive features including expression of PDCD1LG2 (CD273) and CD274, which encode ligands of PD-1 responsible for T cell exhaustion, and of CXCL10 and CCL8, which encode chemokines known to attract CD8 T cells and regulatory T cells, respectively (Griffith et al., 2014) (Figure 6E)....
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...…immunosuppressive features including expression of PDCD1LG2 (CD273) and CD274, which encode ligands of PD-1 responsible for T cell exhaustion, and of CXCL10 and CCL8, which encode chemokines known to attract CD8+ T cells and regulatory T cells, respectively (Griffith et al., 2014) (Figure 6E)....
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TL;DR: An integrated RNA-sequencing approach demonstrates that CXCL13+ TH1-like cells are preferentially enriched in microsatellite-instable tumours from patients with colorectal cancer, and IGFLR1 is identified as a co-stimulatory molecule.
Abstract: T cells are key elements of cancer immunotherapy1 but certain fundamental properties, such as the development and migration of T cells within tumours, remain unknown. The enormous T cell receptor (TCR) repertoire, which is required for the recognition of foreign and self-antigens2, could serve as lineage tags to track these T cells in tumours3. Here we obtained transcriptomes of 11,138 single T cells from 12 patients with colorectal cancer, and developed single T cell analysis by RNA sequencing and TCR tracking (STARTRAC) indices to quantitatively analyse the dynamic relationships among 20 identified T cell subsets with distinct functions and clonalities. Although both CD8+ effector and ‘exhausted’ T cells exhibited high clonal expansion, they were independently connected with tumour-resident CD8+ effector memory cells, implicating a TCR-based fate decision. Of the CD4+ T cells, most tumour-infiltrating T regulatory (Treg) cells showed clonal exclusivity, whereas certain Treg cell clones were developmentally linked to several T helper (TH) cell clones. Notably, we identified two IFNG+ TH1-like cell clusters in tumours that were associated with distinct IFNγ-regulating transcription factors —the GZMK+ effector memory T cells, which were associated with EOMES and RUNX3, and CXCL13+BHLHE40+ TH1-like cell clusters, which were associated with BHLHE40. Only CXCL13+BHLHE40+ TH1-like cells were preferentially enriched in patients with microsatellite-instable tumours, and this might explain their favourable responses to immune-checkpoint blockade. Furthermore, IGFLR1 was highly expressed in both CXCL13+BHLHE40+ TH1-like cells and CD8+ exhausted T cells and possessed co-stimulatory functions. Our integrated STARTRAC analyses provide a powerful approach to dissect the T cell properties in colorectal cancer comprehensively, and could provide insights into the dynamic relationships of T cells in other cancers. An integrated RNA-sequencing approach demonstrates that CXCL13+ TH1-like cells are preferentially enriched in microsatellite-instable tumours from patients with colorectal cancer, and IGFLR1 is identified as a co-stimulatory molecule.
624 citations
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TL;DR: It is shown that expression of CCR7, a chemokine receptor that controls homing to secondary lymphoid organs, divides human memory T cells into two functionally distinct subsets, which are named central memory (TCM) and effector memory (TEM).
Abstract: Naive T lymphocytes travel to T-cell areas of secondary lymphoid organs in search of antigen presented by dendritic cells. Once activated, they proliferate vigorously, generating effector cells that can migrate to B-cell areas or to inflamed tissues. A fraction of primed T lymphocytes persists as circulating memory cells that can confer protection and give, upon secondary challenge, a qualitatively different and quantitatively enhanced response. The nature of the cells that mediate the different facets of immunological memory remains unresolved. Here we show that expression of CCR7, a chemokine receptor that controls homing to secondary lymphoid organs, divides human memory T cells into two functionally distinct subsets. CCR7- memory cells express receptors for migration to inflamed tissues and display immediate effector function. In contrast, CCR7+ memory cells express lymph-node homing receptors and lack immediate effector function, but efficiently stimulate dendritic cells and differentiate into CCR7- effector cells upon secondary stimulation. The CCR7+ and CCR7- T cells, which we have named central memory (TCM) and effector memory (TEM), differentiate in a step-wise fashion from naive T cells, persist for years after immunization and allow a division of labour in the memory response.
5,537 citations
TL;DR: The key features of the life of a neutrophil are discussed, from its release from bone marrow to its death, and the mechanisms that are used by neutrophils to promote protective or pathological immune responses at different sites are explained.
Abstract: Neutrophils have traditionally been thought of as simple foot soldiers of the innate immune system with a restricted set of pro-inflammatory functions. More recently, it has become apparent that neutrophils are, in fact, complex cells capable of a vast array of specialized functions. Although neutrophils are undoubtedly major effectors of acute inflammation, several lines of evidence indicate that they also contribute to chronic inflammatory conditions and adaptive immune responses. Here, we discuss the key features of the life of a neutrophil, from its release from bone marrow to its death. We discuss the possible existence of different neutrophil subsets and their putative anti-inflammatory roles. We focus on how neutrophils are recruited to infected or injured tissues and describe differences in neutrophil recruitment between different tissues. Finally, we explain the mechanisms that are used by neutrophils to promote protective or pathological immune responses at different sites.
3,898 citations
"Chemokines and Chemokine Receptors:..." refers background in this paper
...The concept of sentinel neutrophils being recruited into peripheral tissue in homeostasis is intriguing, and in homeostasis neutrophils may be actively crawling along and patrolling the lung vasculature, but not the spleen or liver (29)....
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TL;DR: Using a murine adoptive transfer system to probe monocyte homing and differentiation in vivo, two functional subsets among murine blood monocytes are identified: a short-lived CX(3)CR1(lo)CCR2(+)Gr1(+) subset that is actively recruited to inflamed tissues and a CX (3) CR1(hi)CCS1-dependent recruitment to noninflamed tissues.
3,307 citations
"Chemokines and Chemokine Receptors:..." refers background in this paper
...Conversely, the anti-inflammatory (CX3CR1+) population was distributed in the peripheral blood and nonlymphoid organs of recipient mice (40)....
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TL;DR: It is shown that injury releases mitochondrial DAMPs into the circulation with functionally important immune consequences, including formyl peptides and mitochondrial DNA, which promote PMN Ca2+ flux and phosphorylation of mitogen-activated protein (MAP) kinases, thus leading to PMN migration and degranulation in vitro and in vivo.
Abstract: Injury causes a systemic inflammatory response syndrome (SIRS) that is clinically much like sepsis. Microbial pathogen-associated molecular patterns (PAMPs) activate innate immunocytes through pattern recognition receptors. Similarly, cellular injury can release endogenous 'damage'-associated molecular patterns (DAMPs) that activate innate immunity. Mitochondria are evolutionary endosymbionts that were derived from bacteria and so might bear bacterial molecular motifs. Here we show that injury releases mitochondrial DAMPs (MTDs) into the circulation with functionally important immune consequences. MTDs include formyl peptides and mitochondrial DNA. These activate human polymorphonuclear neutrophils (PMNs) through formyl peptide receptor-1 and Toll-like receptor (TLR) 9, respectively. MTDs promote PMN Ca(2+) flux and phosphorylation of mitogen-activated protein (MAP) kinases, thus leading to PMN migration and degranulation in vitro and in vivo. Circulating MTDs can elicit neutrophil-mediated organ injury. Cellular disruption by trauma releases mitochondrial DAMPs with evolutionarily conserved similarities to bacterial PAMPs into the circulation. These signal through innate immune pathways identical to those activated in sepsis to create a sepsis-like state. The release of such mitochondrial 'enemies within' by cellular injury is a key link between trauma, inflammation and SIRS.
2,932 citations
"Chemokines and Chemokine Receptors:..." refers background in this paper
...These mitochondrial formyl peptides bind to the formyl peptide receptor 1 (FPR1) and promote neutrophil chemotaxis to the site of cellular injury (94, 95)....
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...Endogenous formyl peptides are produced by mitochondria and can be released upon cellular damage (95)....
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TL;DR: In this paper, the chemokine receptor CCR7 was identified as an important organizer of the primary immune response in mice, and severely delayed kinetics regarding the antibody response and lack contact sensitivity and delayed type hypersensitivity reactions.
2,388 citations