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.
Chemoattractants are pivotal mediators of host defense, orchestrating the recruitment of immune cells into sites of infection and inflammation. Chemoattractants display vast chemical diversity and ...include bioactive lipids, proteolytic fragments of serum proteins, and chemokines (chemotactic cytokines). All chemoattractants induce chemotaxis by activating seven-transmembrane-spanning GPCRs expressed on immune cells, establishing the concept that all chemoattractants are related in function. However, although chemoattractants have overlapping functions in vitro, recent in vivo data have revealed that they function, in many cases, nonredundantly in vivo. The chemically diverse nature of chemoattractants contributes to the fine control of leukocyte trafficking in vivo, with sequential chemoattractant use guiding immune cell recruitment into inflammatory sites. Lipid mediators frequently function as initiators of leukocyte recruitment, attracting the first immune cells into tissues. These initial responding immune cells produce cytokines locally, which in turn, induce the local release of chemokines. Local chemokine production then markedly amplifies subsequent waves of leukocyte recruitment. These new discoveries establish a paradigm for leukocyte recruitment in inflammation--described as lipid-cytokine-chemokine cascades--as a driving force in the effector phase of immune responses.
Chemokines and the immune response to cancer Ozga, Aleksandra J.; Chow, Melvyn T.; Luster, Andrew D.
Immunity (Cambridge, Mass.),
05/2021, Letnik:
54, Številka:
5
Journal Article
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Chemokines are chemotactic cytokines that regulate the migration of immune cells. Chemokines function as cues for the coordinated recruitment of immune cells into and out of tissue and also guide the ...spatial organization and cellular interactions of immune cells within tissues. Chemokines are critical in directing immune cell migration necessary to mount and then deliver an effective anti-tumor immune response; however, chemokines also participate in the generation and recruitment of immune cells that contribute to a pro-tumorigenic microenvironment. Here, we review the role of the chemokine system in anti-tumor and pro-tumor immune responses and discuss how malignant cells and the tumor microenvironment regulate the overall chemokine landscape to shape the type and outcome of immune responses to cancer and cancer treatment.
Luster and colleagues review the role of the chemokine system in anti-tumor and pro-tumor immune responses and discuss how malignant cells and the tumor microenvironment regulate the overall chemokine landscape to shape the type and outcome of immune responses to cancer and cancer treatment.
CXCR3 is a chemokine receptor that is rapidly induced on naïve T cells following activation, and preferentially remains highly expressed on type-1 helper (Th1)-type CD4(+) T cells, effector CD8(+) T ...cells and innate-type lymphocytes, such as natural killer (NK) and NKT cells. CXCR3 is activated by three interferon (IFN)-γ-inducible ligands CXCL9 (monokine induced by gamma-interferon), CXCL10 (interferon-induced protein-10) and CXCL11 (interferon-inducible T-cell alpha chemoattractant). Although some studies have revealed that these ligands have redundant functions in vivo, other studies have demonstrated that the three CXCR3 ligands can also collaborate and even compete with each other. Differential regulation of the three ligands at specific times in defined anatomically restricted locations in vivo likely participates in the fine control of T-cell trafficking over the course of an immune response. Among the differences in regulation, CXCL10 is induced by a variety of innate stimuli that induce IFN-α/β as well as the adaptive immune cell cytokine IFN-γ, whereas CXCL9 induction is restricted to IFN-γ. In this review, we will discuss how the balance, timing and pattern of CXCR3 ligand expression appears to regulate the generation of effector T cells in the lymphoid compartment and subsequent migration into peripheral sites of Th1-type inflammation in which the CXCR3 ligands also then regulate the interactions and migratory behavior of effector T cells in an inflamed peripheral tissue.
Chemokines in cancer Chow, Melvyn T; Luster, Andrew D
Cancer immunology research
2, Številka:
12
Journal Article
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Chemokines are chemotactic cytokines that control the migration of cells between tissues and the positioning and interactions of cells within tissue. The chemokine superfamily consists of ...approximately 50 endogenous chemokine ligands and 20 G protein-coupled seven-transmembrane spanning signaling receptors. Chemokines mediate the host response to cancer by directing the trafficking of leukocytes into the tumor microenvironment. This migratory response is complex and consists of diverse leukocyte subsets with both antitumor and protumor activities. Although chemokines were initially appreciated as important mediators of immune cell migration, we now know that they also play important roles in the biology of nonimmune cells important for tumor growth and progression. Chemokines can directly modulate the growth of tumors by inducing the proliferation of cancer cells and preventing their apoptosis. They also direct tumor cell movement required for metastasis. Chemokines can also indirectly modulate tumor growth through their effects on tumor stromal cells and by inducing the release of growth and angiogenic factors from cells in the tumor microenvironment. In this Masters of Immunology primer, we focus on recent advances in understanding the complex nature of the chemokine system in tumor biology with a focus on how the chemokine system could be used to augment cancer immunotherapeutic strategies to elicit a more robust and long-lasting host antitumor immune response.
The chemokine system in innate immunity Sokol, Caroline L; Luster, Andrew D
Cold Spring Harbor perspectives in biology,
05/2015, Letnik:
7, Številka:
5
Journal Article
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Chemokines are chemotactic cytokines that control the migration and positioning of immune cells in tissues and are critical for the function of the innate immune system. Chemokines control the ...release of innate immune cells from the bone marrow during homeostasis as well as in response to infection and inflammation. They also recruit innate immune effectors out of the circulation and into the tissue where, in collaboration with other chemoattractants, they guide these cells to the very sites of tissue injury. Chemokine function is also critical for the positioning of innate immune sentinels in peripheral tissue and then, following innate immune activation, guiding these activated cells to the draining lymph node to initiate and imprint an adaptive immune response. In this review, we will highlight recent advances in understanding how chemokine function regulates the movement and positioning of innate immune cells at homeostasis and in response to acute inflammation, and then we will review how chemokine-mediated innate immune cell trafficking plays an essential role in linking the innate and adaptive immune responses.
Despite compelling rates of durable clinical responses to programmed cell death-1 (PD-1) blockade, advances are needed to extend these benefits to resistant tumors. We found that tumor-bearing mice ...deficient in the chemokine receptor CXCR3 responded poorly to anti-PD-1 treatment. CXCR3 and its ligand CXCL9 were critical for a productive CD8+ T cell response in tumor-bearing mice treated with anti-PD-1 but were not required for the infiltration of CD8+ T cells into tumors. The anti-PD-1-induced anti-tumor response was facilitated by CXCL9 production from intratumoral CD103+ dendritic cells, suggesting that CXCR3 facilitates dendritic cell-T cell interactions within the tumor microenvironment. CXCR3 ligands in murine tumors and in plasma of melanoma patients were an indicator of clinical response to anti-PD-1, and their induction in non-responsive murine tumors promoted responsiveness to anti-PD-1. Our data suggest that the CXCR3 chemokine system is a biomarker for sensitivity to PD-1 blockade and that augmenting the intratumoral function of this chemokine system could improve clinical outcomes.
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•Anti-PD-1 efficacy depends on intratumoral activity of the CXCR3 chemokine system•CD103+ dendritic-cell-derived CXCL9 and CXCR3 on CD8+ T cells are required•CXCR3 ligands are positive indicators of responsiveness to anti-PD-1 therapy•Inducing CXCR3 ligands in non-responsive tumors restores sensitivity to anti-PD-1
Chow et al. find the CXCR3 chemokine system is not required for CD8+ T cell migration into the tumor, but rather for the enhancement of the intratumoral CD8+ T cell response in the context of PD-1 blockade. The CXCR3 chemokine system might serve as a biomarker for sensitivity to PD-1 blockade and a target for improving clinical outcomes.
Stromal cells (SCs) establish the compartmentalization of lymphoid tissues critical to the immune response. However, the full diversity of lymph node (LN) SCs remains undefined. Using droplet-based ...single-cell RNA sequencing, we identified nine peripheral LN non-endothelial SC clusters. Included are the established subsets, Ccl19hi T-zone reticular cells (TRCs), marginal reticular cells, follicular dendritic cells (FDCs), and perivascular cells. We also identified Ccl19lo TRCs, likely including cholesterol-25-hydroxylase+ cells located at the T-zone perimeter, Cxcl9+ TRCs in the T-zone and interfollicular region, CD34+ SCs in the capsule and medullary vessel adventitia, indolethylamine N-methyltransferase+ SCs in the medullary cords, and Nr4a1+ SCs in several niches. These data help define how transcriptionally distinct LN SCs support niche-restricted immune functions and provide evidence that many SCs are in an activated state.
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•Single-cell RNA sequencing of lymph node stromal cells reveals nine clusters•Known subsets TRCs, MRCs, FDCs, and perivascular cells identified•Five additional stromal cell clusters identified and anatomical locations determined•Two clusters, Cxcl9+ TRCs and Nr4a1+ SCs, are defined by activation signatures
Lymph node stromal cells support diverse processes, but bulk assessments obscure their niche-specific functions. Rodda et al. identify transcriptional profiles for nine lymph node stromal cell clusters using single-cell RNA sequencing, validate subset markers in situ, and suggest niche-restricted functions.
CXCR3 in T cell function Groom, Joanna R.; Luster, Andrew D.
Experimental cell research,
03/2011, Letnik:
317, Številka:
5
Journal Article
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CXCR3 is a chemokine receptor that is highly expressed on effector T cells and plays an important role in T cell trafficking and function. CXCR3 is rapidly induced on naïve cells following activation ...and preferentially remains highly expressed on Th1-type CD4+ T cells and effector CD8+ T cells. CXCR3 is activated by three interferon-inducible ligands CXCL9 (MIG), CXCL10 (IP-10) and CXCL11 (I-TAC). Early studies demonstrated a role for CXCR3 in the trafficking of Th1 and CD8 T cells to peripheral sites of Th1-type inflammation and the establishment of a Th1 amplification loop mediated by IFNγ and the IFNγ-inducible CXCR3 ligands. More recent studies have also suggested that CXCR3 plays a role in the migration of T cells in the microenvironment of the peripheral tissue and lymphoid compartment, facilitating the interaction of T cells with antigen presenting cells leading to the generation of effector and memory cells.
Differentiation of naive CD4+ T cells into T helper (Th) cells is a defining event in adaptive immunity. The cytokines and transcription factors that control Th cell differentiation are understood, ...but it is not known how this process is orchestrated within lymph nodes (LNs). Here we have shown that the CXCR3 chemokine receptor was required for optimal generation of interferon-γ (IFN-γ)-secreting Th1 cells in vivo. By using a CXCR3 ligand reporter mouse, we found that stromal cells predominately expressed the chemokine ligand CXCL9 whereas hematopoietic cells expressed CXCL10 in LNs. Dendritic cell (DC)-derived CXCL10 facilitated T cell-DC interactions in LNs during T cell priming while both chemokines guided intranodal positioning of CD4+ T cells to interfollicular and medullary zones. Thus, different chemokines acting on the same receptor can function locally to facilitate DC-T cell interactions and globally to influence intranodal positioning, and both functions contribute to Th1 cell differentiation.
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► CXCR3 is required on CD4+ T cells for optimal Th1 cell differentiation in vivo ► CXCL9 and CXCL10 are both required for optimal Th1 cell IFN-γ production in vivo ► CXCR3 enhances T cell-DC interactions in LNs for optimal Th1 cell differentiation ► CXCR3 positions priming T cells in LNs for optimal Th1 cell differentiation
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