Macrophages are present in all vertebrate tissues, from mid-gestation throughout life, constituting a widely dispersed organ system. They promote homeostasis by responding to internal and external changes within the body, not only as phagocytes in defence against microbes and in clearance of dead and senescent cells, but also through trophic, regulatory and repair functions. In this review, we describe macrophage phenotypic heterogeneity in different tissue environments, drawing particular attention to organ-specific functions.

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Tissue macrophages: heterogeneity and functions

Chemokines are small secreted proteins that orchestrate migration and positioning of immune cells within the tissues. Chemokines are essential for the function of the immune system. Accumulating evidence suggest that chemokines play important roles in tumor microenvironment. In this review we discuss an association of chemokine expression and activity within the tumor microenvironment with cancer outcome. We summarize regulation of immune cell recruitment into the tumor by chemokine-chemokine receptor interactions and describe evidence implicating chemokines in promotion of the “inflamed” immune-cell enriched tumor microenvironment. We review both tumor-promoting function of chemokines, such as regulation of tumor metastasis, and beneficial chemokine roles, including stimulation of anti-tumor immunity and response to immunotherapy. Finally, we discuss the therapeutic strategies target tumor-promoting chemokines or induce/deliver beneficial chemokines within the tumor focusing on pre-clinical studies and clinical trials going forward. The goal of this review is to provide insight into comprehensive role of chemokines and their receptors in tumor pathobiology and treatment.

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Chemokines Modulate Immune Surveillance in Tumorigenesis, Metastasis, and Response to Immunotherapy.

Innate lymphoid cells (ILCs) are enriched at barrier surfaces of the mammalian body where they rapidly respond to host, microbial or environmental stimuli to promote immunity or tissue homeostasis. Furthermore, ILCs are dysregulated in multiple human diseases. Over the past decade, substantial advances have been made in identifying the heterogeneity and functional diversity of ILCs, which have revealed striking similarities to T cell subsets. However, emerging evidence indicates that ILCs also have a complex role in directly influencing the adaptive immune response in the context of development, homeostasis, infection or inflammation. In turn, adaptive immunity reciprocally regulates ILCs, which indicates that these interactions are a crucial determinant of immune responses within tissues. Here, we summarize our current understanding of functional interactions between ILCs and the adaptive immune system, discuss limitations and future areas of investigation, and consider the potential for these interactions to be therapeutically harnessed to benefit human health. This Review focuses on evidence implicating innate lymphoid cells (ILCs) as previously unappreciated regulators of the adaptive immune system. Reciprocal interactions between ILCs and adaptive immune cells are a crucial determinant of tissue immune responses during homeostasis and disease.

Functional interactions between innate lymphoid cells and adaptive immunity

Single-Cell Survey of Human Lymphatics Unveils Marked Endothelial Cell Heterogeneity and Mechanisms of Homing for Neutrophils.

The influx and efflux of cells and antigens to and from the draining lymph nodes largely take place through the subcapsular, cortical and medullary sinus systems. Recent analyses in mice and humans have revealed unexpected diversity in the lymphatic endothelial cells, which form the distinct regions of the sinuses. As a semipermeable barrier, the lymphatic endothelial cells regulate the sorting of lymph-borne antigens to the lymph node parenchyma and can themselves serve as antigen-presenting cells. The leukocytes entering the lymph node via the sinus system and the lymphocytes egressing from the parenchyma migrate through the lymphatic endothelial cell layer. The sinus lymphatic endothelial cells also orchestrate the organogenesis of lymph nodes, and they undergo bidirectional signalling with other sinus-resident cells, such as subcapsular sinus macrophages, to generate a unique lymphatic niche. In this Review, we consider the structural and functional basis of how the lymph node sinus system coordinates immune responses under physiological conditions, and in inflammation and cancer.

Lymphatic endothelial cells of the lymph node.

Lymph nodes (LNs) contain innate-like lymphocytes that survey the subcapsular sinus (SCS) and associated macrophages for pathogen entry. The factors promoting this surveillance behavior have not been defined. Here, we report that IL7R(hi)Ccr6(+) lymphocytes in mouse LNs rapidly produce IL17 upon bacterial and fungal challenge. We show that these innate-like lymphocytes are mostly LN resident. Ccr6 is required for their accumulation near the SCS and for efficient IL17 induction. Migration into the SCS intrinsically requires S1pr1, whereas movement from the sinus into the parenchyma involves the integrin LFA1 and its ligand ICAM1. CD169, a sialic acid-binding lectin, helps retain the cells within the sinus, preventing their loss in lymph flow. These findings establish a role for Ccr6 in augmenting innate-like lymphocyte responses to lymph-borne pathogens, and they define requirements for cell movement between parenchyma and SCS in what we speculate is a program of immune surveillance that helps achieve LN barrier immunity.

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Migratory and adhesive cues controlling innate-like lymphocyte surveillance of the pathogen-exposed surface of the lymph node

While young blood can restore many aged tissues, its effects on the aged blood system itself and old hematopoietic stem cells (HSCs) have not been determined. Here, we used transplantation, parabiosis, plasma transfer, exercise, calorie restriction, and aging mutant mice to understand the effects of age-regulated systemic factors on HSCs and their bone marrow (BM) niche. We found that neither exposure to young blood, nor long-term residence in young niches after parabiont separation, nor direct heterochronic transplantation had any observable rejuvenating effects on old HSCs. Likewise, exercise and calorie restriction did not improve old HSC function, nor old BM niches. Conversely, young HSCs were not affected by systemic pro-aging conditions, and HSC function was not impacted by mutations influencing organismal aging in established long-lived or progeroid genetic models. Therefore, the blood system that carries factors with either rejuvenating or pro-aging properties for many other tissues is itself refractory to those factors.

Patrick Ventura

Papers

Migratory and adhesive cues controlling innate-like lymphocyte surveillance of the pathogen-exposed surface of the lymph node

Aged hematopoietic stem cells are refractory to bloodborne systemic rejuvenation interventions.