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In mice, γδ-T lymphocytes that express the co-stimulatory molecule, CD27, are committed to the IFNγ-producing lineage during thymic development. In the periphery, these cells play a critical role in host defense and anti-tumor immunity. Unlike αβ-T cells that rely on MHC-presented peptides to drive their terminal differentiation, it is unclear whether MHC-unrestricted γδ-T cells undergo further functional maturation after exiting the thymus. Here, we provide evidence of phenotypic and functional diversity within peripheral IFNγ-producing γδ T cells. We found that CD27+ Ly6C− cells convert into CD27+Ly6C+ cells, and these CD27+Ly6C+ cells control cancer progression in mice, while the CD27+Ly6C− cells cannot. The gene signatures of these two subsets were highly analogous to human immature and mature γδ-T cells, indicative of conservation across species. We show that IL-27 supports the cytotoxic phenotype and function of mouse CD27+Ly6C+ cells and human Vδ2+ cells, while IL-27 is dispensable for mouse CD27+Ly6C− cell and human Vδ1+ cell functions. These data reveal increased complexity within IFNγ-producing γδ-T cells, comprising immature and terminally differentiated subsets, that offer new insights into unconventional T-cell biology. Synopsis: Mouse IFNγ-producing γδ-T cells are potent cancer-killing cells; however, their diversity and regulation by cytokines is poorly understood. This study shows that CD27+Ly6C+ γδ T cells are terminally differentiated cells responsive to IL-27 that originate from immature CD27+ Ly6C- γδ T cells. The cell surface marker, Ly6C, defines a cytotoxic and terminally differentiated CD27+ γδ T cell subset. Compared to CD27+Ly6C- γδ T cells, CD27+Ly6C+ γδ T cells are characterized by transcription factor T-bet, IFNγ, and CD44 expression as well as high levels of additional cytotoxic molecules. CD27+Ly6C+ γδ T cells are more proficient for killing cancer cells than CD27+Ly6C- γδ T cells and can slow tumor growth in vivo. The conversion of immature CD27+Ly6C- γδ T cells into CD27+Ly6C+ γδ T cells is concomitant with acquisition of their cytotoxic profile. IL-27 supports the cytotoxic phenotype of mouse CD27+Ly6C+ γδ T cells and human Vδ2+ γδ T cells. Mouse IFNγ-producing γδ T cells have functional diversity similar to humans, with IL-27 important for cytotoxic phenotype in more mature γδ T cells. [ABSTRACT FROM AUTHOR]

The immune system plays fundamental roles in the mammary gland, shaping developmental processes and controlling inflammation during infection and cancer.Here, we reveal unanticipated heterogeneity in the myeloid cell compartment duringdevelopment of virgin, pregnant, lactating and involuting mouse mammary glands,and in milk. We investigate the functional consequences of individual and compoundchemokine receptor deficiency on cell recruitment. Diverse myeloid cell recruitmentwas also shown in models of sterile inflammation and bacterial infection.Strikingly, we have shown that inflammation and infection can alter the abundanceof terminal end buds, a key developmental structure, within the pubertal mammarygland. This previously unknown effect of inflammatory burden during puberty couldhave important implications for understanding pubertal development. [ABSTRACT FROM AUTHOR]

Analysis of chemokine receptor, and atypical chemokine receptor, expression is frequently hampered by the lack of availability of high‐quality antibodies and the species specificity of those that are available. We have previously described methodology utilizing Alexa‐Fluor‐labeled chemokine ligands as versatile reagents to detect receptor expression. Previously this has been limited to hematopoietic cells and methodology for assessing expression of receptors on stromal cells has been lacking. Among chemokine receptors, the ones most frequently expressed on stromal cells belong to the atypical chemokine receptor subfamily. These receptors do not signal in the classic sense in response to ligand but scavenge their ligands and degrade them and thus sculpt in vivo chemokine gradients. Here, we demonstrate the ability to use either intratracheal or intravenous, Alexa‐Fluor‐labeled chemokine administration to detect stromal cell populations expressing the atypical chemokine receptor ACKR2. Using this methodology, we demonstrate, for the first time, expression of ACKR2 on blood endothelial cells. This observation sets the lung aside from other tissues in which ACKR2 is exclusively expressed on lymphatic endothelial cells and suggest unique roles for ACKR2 in the pulmonary environment. [ABSTRACT FROM AUTHOR]

Chemokines and their receptors are essential regulators of in vivo leukocyte migration and, some years ago, a systematic nomenclature system was developed for the chemokine receptor family. Chemokine receptor biology and biochemistry was recently extensively reviewed. In this review, we also highlighted a new component to the nomenclature system that incorporates receptors previously known as 'scavenging', or 'decoy', chemokine receptors on the basis of their lack of classical signalling responses to ligand binding and their general ability to scavenge, or sequester, their cognate chemokine ligands. These molecules are now collectively referred to as 'atypical chemokine receptors', or ACKRs, and play fundamental roles in regulating in vivo responses to chemokines. This commentary highlights this new addition to the chemokine receptor nomenclature system and provides brief information on the four receptors currently covered by this nomenclature. [ABSTRACT FROM AUTHOR]

Macrophages regulate lymphatic vasculature development; however, the molecular mechanisms regulating their recruitment to developing, and adult, lymphatic vascular sites are not known. Here, we report that resting mice deficient for the inflammatory chemokine-scavenging receptor, ACKR2, display increased lymphatic vessel density in a range of tissues under resting and regenerating conditions. This appears not to alter dendritic cell migration to draining lymph nodes but is associated with enhanced fluid drainage from peripheral tissues and thus with a hypotensive phenotype. Examination of embryonic skin revealed that this lymphatic vessel density phenotype is developmentally established. Further studies indicated that macrophages and the inflammatory CC-chemokine CCL2, which is scavenged by ACKR2, are associated with this phenotype. Accordingly, mice deficient for the CCL2 signalling receptor, CCR2, displayed a reciprocal phenotype of reduced lymphatic vessel density. Further examination revealed that proximity of pro-lymphangiogenic macrophages to developing lymphatic vessel surfaces is increased in ACKR2-deficient mice and reduced in CCR2-deficient mice. Therefore, these receptors regulate vessel density by reciprocally modulating pro-lymphangiogenic macrophage recruitment, and proximity, to developing, resting and regenerating lymphatic vessels. [ABSTRACT FROM AUTHOR]

Chemokine receptors play an important role in leukocyte migration, both in physiological and pathological conditions, and the interest in new methodologies for their detection is increasing. In this review, we focused on chemokine receptors detection through flow cytometric approaches, including the use of specific antibodies and fluorescent chemokines, and on approaches aimed at the analysis of their functions, from intracellular trafficking to signaling activities. © 2014 International Society for Advancement of Cytometry [ABSTRACT FROM AUTHOR]

Chemokines and their receptors are key regulators of leukocyte migration and intra-tissue accumulation under both homeostatic and inflammatory conditions. Regulation of chemokine-dependent responses, particularly those relating to inflammation, is essential to avoid the development of inflammatory and autoimmune pathologies. Recently, a new subfamily of chemokine receptors referred to as the 'atypical' chemokine receptors has emerged, members of which have been shown to play important roles in controlling in vivo chemokine biology. Here we review the basic biology of the chemokine and chemokine receptor family, introduce the topic of 'atypical' chemokine receptor biology and focus specifically on the best-characterized of the 'atypical' chemokine receptors, D6. D6 is a 'scavenging' receptor for inflammatory CC chemokines and plays a central role in the resolution of in vivo inflammatory responses. We describe the biology, biochemistry and pathological relevance of D6 and outline emerging data suggesting that it has additional important roles in integrating innate and adaptive immune responses. [ABSTRACT FROM AUTHOR]

Chronic lymphocytic leukaemia (CLL) is a malignancy of CD5+ B cells. This B-cell lineage is established during ontogeny and replenished by the process of self-renewal. Spontaneous and induced leukaemias that frequently affect this lineage are thought to arise as a result of the frequent cell division required to maintain the population throughout adulthood and in response to repeated exposure to environmental antigens. In a series of bone marrow transplant (BMT) experiments performed in B6D2F1 mice, B-cell leukaemia occurred in recipients of serially transplanted syngeneic bone marrow. This study was therefore designed to determine the frequency and phenotype of the observed leukaemia. Male donor cells were initially transplanted into lethally irradiated female hosts and secondary (2°) BMT was performed at 3 months. At 1, 2, 3 and 16 months following primary (1°) BMT, and when 2° BMT recipients developed leukaemia, animals were sacrificed and their tissues extensively examined. These analyses confirmed a host-derived CD5+ transplantable B-cell leukaemia that was initiated in 50% of 1° BMT recipients. With serial passage, the leukaemia became more aggressive and lost CD5 expression, suggesting transformation to a high-grade leukaemia/lymphoma. This previously unreported observation suggests that the combination of radiation and subsequent serial transplantation induces a proliferative stress to the host B-cell compartment that is causative in leukaemic transformation. [ABSTRACT FROM AUTHOR]