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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]

ACKR3 scavenges and degrades the stem cell recruiting chemokine CXCL12, which is essential for proper embryonic and, in particular, haematopoietic development. Here, we demonstrate strong expression of ACKR3 on trophoblasts. Using a maternally administered pharmacological blocker and Cre-mediated genetic approaches, we demonstrate that trophoblast ACKR3 is essential for preventing movement of CXCL12 from the mother to the embryo, with elevated plasma CXCL12 levels being detected in embryos from ACKR3-blocker-treated mothers. Mice born to mothers treated with the blocker are lighter and shorter than those born to vehicle-treated mothers and, in addition, display profound anaemia associated with a markedly reduced bone marrow haematopoietic stem cell population. Importantly, although the haematopoietic abnormalities are corrected as mice age, our studies reveal a postnatal window during which offspring of ACKR3-blocker-treated mice are unable to mount effective inflammatory responses to inflammatory/infectious stimuli. Overall, these data demonstrate that ACKR3 is essential for preventing CXCL12 transfer from mother to embryo and for ensuring properly regulated CXCL12 control over the development of the haematopoietic system. [ABSTRACT FROM AUTHOR]

Chemokines regulate leukocyte navigation to inflamed sites and specific tissue locales and may therefore be useful for ensuring accurate homing of cell therapeutic products. We, and others, have shown that atypical chemokine receptor 2 (ACKR2), deficient mice (ACKR2-/-) are protected from metastasis development in cell line and spontaneous mouse models. We have shown that this relates to enhanced CCR2 expression on ACKR2-/- NK cells allowing them to home more effectively to CCR2 ligand expressing metastatic deposits. Here we demonstrate that the metastatic-suppression phenotype in ACKR2-/- mice is not a direct effect of the absence of ACKR2. Instead, enhanced NK cell CCR2 expression is caused by passenger-mutations that originate from creation of the ACKR2-/- mouse strain in 129 embryonic stem cells. We further demonstrate that simple selection of CCR2+ NK cells enriches for a population of cells with enhanced anti-metastatic capabilities. Given the widespread expression of CCR2 ligands by tumors, our study highlights CCR2 as a potentially important contributor to NK cell tumoricidal cell therapy., (© The Author(s) 2024. Published by Oxford University Press on behalf of Society for Leukocyte Biology.)

The interactions between chemokines and their receptors, particularly in the context of inflammation, are complex, with individual receptors binding multiple ligands and individual ligands interacting with multiple receptors. In addition, there are numerous reports of simultaneous coexpression of multiple inflammatory chemokine receptors on individual inflammatory leukocyte subtypes. Overall, this has previously been interpreted as redundancy and proposed as a protective mechanism to ensure that the inflammatory response is robust. By contrast, we have hypothesized that the system is not redundant but exquisitely subtle. Our interests relate to the receptors CCR1, CCR2, CCR3, and CCR5, which, together, regulate nonneutrophilic myeloid cell recruitment to inflammatory sites. In this study, we demonstrate that although most murine monocytes exclusively express CCR2, there is a small subpopulation that is expanded during inflammation and coexpresses CCR1 and CCR2. Combinations of transcript and functional analysis demonstrate that this is not redundant expression and that coexpression of CCR1 and CCR2 marks a phenotypically distinct population of monocytes characterized by expression of genes otherwise typically associated with neutrophils. Single-cell RNA sequencing confirms this as a monodisperse population of atypical monocytes. This monocytic population has previously been described as having immunosuppressive activity. Overall, our data confirm combinatorial chemokine receptor expression by a subpopulation of monocytes but demonstrate that this is not redundant expression and marks a discrete monocytic population., (Copyright © 2024 The Authors.)