The Experts below are selected from a list of 1698 Experts worldwide ranked by ideXlab platform
Elixabet Bolanos - One of the best experts on this subject based on the ideXlab platform.
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intratumoral immunotherapy with XCL1 and sflt3l encoded in recombinant semliki forest virus derived vectors fosters dendritic cell mediated t cell cross priming
Cancer Research, 2018Co-Authors: Alfonso R Sanchezpaulete, Alvaro Teijeira, Jose I Quetglas, Maria E Rodriguezruiz, Alvaro Sanchezarraez, Sara Labiano, Inaki Etxeberria, Arantza Azpilikueta, Elixabet BolanosAbstract:: Multiple lines of evidence indicate a critical role of antigen cross-presentation by conventional BATF3-dependent type 1 classical dendritic cells (cDC1) in CD8-mediated antitumor immunity. Flt3L and XCL1, respectively, constitute a key growth/differentiation factor and a potent and specific chemoattractant for cDC1. To exploit their antitumor functions in local immunotherapy, we prepared Semliki Forest Virus (SFV)-based vectors encoding XCL1 and soluble Flt3L (sFlt3L). These vectors readily conferred transgene expression to the tumor cells in culture and when engrafted as subcutaneous mouse tumor models. In syngeneic mice, intratumoral injection of SFV-XCL1-sFlt3L (SFV-XF) delayed progression of MC38- and B16-derived tumors. Therapeutic activity was observed and exerted additive effects in combination with anti-PD-1, anti-CD137, or CTLA-4 immunostimulatory mAbs. Therapeutic effects were abolished by CD8β T-cell depletion and were enhanced by CD4 T-cell depletion, but not by T regulatory cell predepletion with anti-CD25 mAb. Antitumor effects were also abolished in BATF3- and IFNAR-deficient mice. In B16-OVA tumors, SFV-XF increased the number of infiltrating CD8 T cells, including those recognizing OVA. Consistently, following the intratumoral SFV-XF treatment courses, we observed increased BATF3-dependent cDC1 among B16-OVA tumor-infiltrating leukocytes. Such an intratumoral increase was not seen in MC38-derived tumors, but both resident and migratory cDC1 were boosted in SFV-XF-treated MC38 tumor-draining lymph nodes. In conclusion, viral gene transfer of sFlt3L and XCL1 is feasible, safe, and biologically active in mice, exerting antitumor effects that can be potentiated by CD4 T-cell depletion. SIGNIFICANCE: These findings demonstrate that transgenic expression of sFLT3L and XCL1 in tumor cells mediates cross-priming of, and elicits potent antitumor activity from, CD8 T lymphocytes, particularly in combination with CD4 T-cell depletion.
Odette Leiter - One of the best experts on this subject based on the ideXlab platform.
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the systemic exercise released chemokine lymphotactin XCL1 modulates in vitro adult hippocampal precursor cell proliferation and neuronal differentiation
Scientific Reports, 2019Co-Authors: Odette Leiter, Stefanie N Bernas, Suse Seidemann, Rupert W Overall, Cindy Horenburg, Susann KowalAbstract:Physical exercise has well-established anti-inflammatory effects, with neuro-immunological crosstalk being proposed as a mechanism underlying the beneficial effects of exercise on brain health. Here, we used physical exercise, a strong positive modulator of adult hippocampal neurogenesis, as a model to identify immune molecules that are secreted into the blood stream, which could potentially mediate this process. Proteomic profiling of mouse plasma showed that levels of the chemokine lymphotactin (XCL1) were elevated after four days of running. We found that XCL1 treatment of primary cells isolated from both the dentate gyrus and the subventricular zone of the adult mice led to an increase in the number of neurospheres and neuronal differentiation in neurospheres derived from the dentate gyrus. In contrast, primary dentate gyrus cells isolated from XCL1 knockout mice formed fewer neurospheres and exhibited a reduced neuronal differentiation potential. XCL1 supplementation in a dentate gyrus-derived neural precursor cell line promoted neuronal differentiation and resulted in lower cell motility and a reduced number of cells in the S phase of the cell cycle. This work suggests an additional function of the chemokine XCL1 in the brain and underpins the complexity of neuro-immune interactions that contribute to the regulation of adult hippocampal neurogenesis.
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The systemic exercise-released chemokine lymphotactin/XCL1 modulates in vitro adult hippocampal precursor cell proliferation and neuronal differentiation.
Scientific reports, 2019Co-Authors: Odette Leiter, Stefanie N Bernas, Suse Seidemann, Rupert W Overall, Cindy Horenburg, Susann Kowal, Gerd Kempermann, Tara L. WalkerAbstract:Physical exercise has well-established anti-inflammatory effects, with neuro-immunological crosstalk being proposed as a mechanism underlying the beneficial effects of exercise on brain health. Here, we used physical exercise, a strong positive modulator of adult hippocampal neurogenesis, as a model to identify immune molecules that are secreted into the blood stream, which could potentially mediate this process. Proteomic profiling of mouse plasma showed that levels of the chemokine lymphotactin (XCL1) were elevated after four days of running. We found that XCL1 treatment of primary cells isolated from both the dentate gyrus and the subventricular zone of the adult mice led to an increase in the number of neurospheres and neuronal differentiation in neurospheres derived from the dentate gyrus. In contrast, primary dentate gyrus cells isolated from XCL1 knockout mice formed fewer neurospheres and exhibited a reduced neuronal differentiation potential. XCL1 supplementation in a dentate gyrus-derived neural precursor cell line promoted neuronal differentiation and resulted in lower cell motility and a reduced number of cells in the S phase of the cell cycle. This work suggests an additional function of the chemokine XCL1 in the brain and underpins the complexity of neuro-immune interactions that contribute to the regulation of adult hippocampal neurogenesis.
Bjarne Bogen - One of the best experts on this subject based on the ideXlab platform.
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dendritic cell targeted ccl3 and XCL1 fusion dna vaccines differ in induced immune responses and optimal delivery site
Scientific Reports, 2019Co-Authors: Anna Lysen, Arnar Gudjonsson, Bjarne Bogen, Ranveig Braathen, Demo Yemane Tesfaye, Even FossumAbstract:Fusing antigens to chemokines to target antigen presenting cells (APC) is a promising method for enhancing immunogenicity of DNA vaccines. However, it is unclear how different chemokines compare in terms of immune potentiating effects. Here we compare Ccl3- and XCL1-fusion vaccines containing hemagglutinin (HA) from influenza A delivered by intramuscular (i.m.) or intradermal (i.d.) DNA vaccination. XCL1 fusion vaccines target cDC1s, and enhance proliferation of CD4+ and CD8+ T cells in vitro. In contrast, Ccl3 target both cDC1 and cDC2, but only enhance CD4+ T cell proliferation in combination with cDC2. When Ccl3- or XCL1-HA fusion vaccines were administered by i.m. DNA immunization, both vaccines induced Th1-polarized immune responses with antibodies of the IgG2a/IgG2b subclass and IFNγ-secreting T cells. After i.d. DNA vaccination, however, only XCL1-HA maintained a Th1 polarized response and induced even higher numbers of IFNγ-secreting T cells. Consequently, XCL1-HA induced superior protection against influenza infection compared to Ccl3-HA after i.d. immunization. Interestingly, i.m. immunization with Ccl3-HA induced the strongest overall in vivo cytotoxicity, despite not inducing OT-I proliferation in vitro. In summary, our results highlight important differences between Ccl3- and XCL1- targeted DNA vaccines suggesting that chemokine fusion vaccines can be tailor-made for different diseases.
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Data_Sheet_1_Endocytosis Deficient Murine XCL1-Fusion Vaccine Enhances Protective Antibody Responses in Mice.pdf
2019Co-Authors: Arnar Gudjonsson, Tor Kristian Andersen, Vibeke Sundvold-gjerstad, Bjarne Bogen, Even FossumAbstract:Targeting antigen to surface receptors on dendritic cells (DCs) can improve antibody response against subunit vaccines. We have previously observed that human XCL1-fusion vaccines target murine Xcr1+ DCs without actively inducing endocytosis of the antigen, resulting in enhanced antibody responses in mice. However, the use of foreign chemokines for targeting is undesirable when translating this observation to human or veterinary medicine due to potential cross-reactive responses against the endogenous chemokine. Here we have identified a mutant version of murine XCL1, labeled XCL1(Δ1) owing to removal of a conserved valine in position 1 of the mature chemokine, that retains specific binding to Xcr1+ DCs without inducing endocytosis of the receptor. DNA immunization with XCL1(Δ1) conjugated to influenza hemagglutinin (HA) induced improved antibody responses, with higher end point titers of IgG compared to WT XCL1-HA. The XCL1(Δ1) fusion vaccine also resulted in an increased number of HA reactive germinal center B cells with higher avidity toward the antigen, and serum transfer experiments show that XCL1(Δ1)-HA induced antibody responses provided better protection against influenza infection as compared to WT XCL1-HA. In summary, our observations indicate that targeting antigen to Xcr1+ DCs in an endocytosis deficient manner enhances antibody responses. This effect was obtained by introducing a single mutation to XCL1, suggesting our strategy may easily be translated to human or veterinary vaccine settings.
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Endocytosis Deficient Murine XCL1-Fusion Vaccine Enhances Protective Antibody Responses in Mice
Frontiers Media S.A., 2019Co-Authors: Arnar Gudjonsson, Tor Kristian Andersen, Vibeke Sundvold-gjerstad, Bjarne Bogen, Even FossumAbstract:Targeting antigen to surface receptors on dendritic cells (DCs) can improve antibody response against subunit vaccines. We have previously observed that human XCL1-fusion vaccines target murine Xcr1+ DCs without actively inducing endocytosis of the antigen, resulting in enhanced antibody responses in mice. However, the use of foreign chemokines for targeting is undesirable when translating this observation to human or veterinary medicine due to potential cross-reactive responses against the endogenous chemokine. Here we have identified a mutant version of murine XCL1, labeled XCL1(Δ1) owing to removal of a conserved valine in position 1 of the mature chemokine, that retains specific binding to Xcr1+ DCs without inducing endocytosis of the receptor. DNA immunization with XCL1(Δ1) conjugated to influenza hemagglutinin (HA) induced improved antibody responses, with higher end point titers of IgG compared to WT XCL1-HA. The XCL1(Δ1) fusion vaccine also resulted in an increased number of HA reactive germinal center B cells with higher avidity toward the antigen, and serum transfer experiments show that XCL1(Δ1)-HA induced antibody responses provided better protection against influenza infection as compared to WT XCL1-HA. In summary, our observations indicate that targeting antigen to Xcr1+ DCs in an endocytosis deficient manner enhances antibody responses. This effect was obtained by introducing a single mutation to XCL1, suggesting our strategy may easily be translated to human or veterinary vaccine settings
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targeting influenza virus hemagglutinin to xcr1 dendritic cells in the absence of receptor mediated endocytosis enhances protective antibody responses
Journal of Immunology, 2017Co-Authors: Arnar Gudjonsson, Anna Lysen, Sreekumar Balan, Vibeke Sundvoldgjerstad, Catharina Arnoldschrauf, Lisa Richter, Espen S Baekkevold, Marc Dalod, Bjarne BogenAbstract:Targeting Ags to conventional dendritic cells can enhance Ag-specific immune responses. Although most studies have focused on the induction of T cell responses, the mechanisms by which targeting improves Ab responses are poorly understood. In this study we present data on the use of human XCL1 (hXCL1) and hXCL2 fusion vaccines in a murine model. We show that the human chemokines bound type 1 conventional dendritic cells (cDC1), and that immunization with influenza virus hemagglutinin fused to hXCL1 or hXCL2 induced full protection against influenza challenge. Surprisingly, the hXCL1- and hXCL2-fusion vaccines induced better long-term protection associated with stronger induction of neutralizing Abs, and more Ab-secreting cells in bone marrow. In contrast, murine XCL1 fusion vaccines induced stronger CD8+ T cell responses compared with hXCL1. Further analysis revealed that although murine XCL1 fusion vaccines induced chemotaxis and were rapidly endocytosed by cDC1, hXCL1 and hXCL2 fusion vaccines did not induce chemotaxis, were less efficiently endocytosed, and consequently, remained on the surface. This difference may explain the enhanced induction of Abs when targeting Ag to cDC1 using hXCL1 and hXCL2, and suggests that immune responses can be manipulated in directing Abs or T cells based on how efficiently the targeted Ag is endocytosed by the DC.
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abstract a54 laser assisted intradermal delivery of XCL1 specific fusion vaccines induces potent antitumor response
Cancer immunology research, 2015Co-Authors: Dorothea Terhorst, Bjarne Bogen, Even Fossum, Sandrine Henri, Bernard MalissenAbstract:Dendritic cells (DCs) are highly efficient specialized antigen-presenting cells and have been regarded as promising targets in cancer immunotherapy. Cross-presentation of antigen by a subset of DCs, the CD8α-type DCs to CD8+ T cells is a fundamentally important mechanism in the defense against pathogens and tumors. In human and mice, CD8α-type DCs that are able to cross present uniquely express the chemokine receptor Xcr1 that binds the XCL1 chemokine. We targeted antigens to cross- presenting CD8α-type DCs using XCL1 inserted in dimeric vaccine molecules. Bivalent XCL1 fusion vaccines bind specifically to and chemoattract CD8α-type DCs in a Xcr1 dependent manner. With its easy accessibility and rich network of DCs, the skin appeals as a promising target site for vaccination. Using the PLEASE® laser microporation system, we specifically applied XCL1 fusion vaccines into the murine dermis and targeted the cross-presenting CD8α-type dermal DCs. A single application of XCL1 coupled to the modelantigen Ovalbumin (OVA) on the dermis of the mouse ear skin produced enhanced CD4 and CD8 T-cell responses, even in the absence of adjuvants. The first T-cell response was limited to the ear draining lymph node. This suggests that the application of antigens by laser microporation to the ear leads to a first localized immune response and thus limiting the possible amount of systemic side effects. However, such targeting of XCL1-OVA also produced a striking enhancement of antibody responses. When the mice were challenged with B16 melanoma expressing OVA, treatment with the XCL1-OVA could prevent development or mediate eradication of subcutaneous solid B16-OVA melanoma. We conclude that targeting of dimeric fusion vaccine molecules to dermal CD8α-type DCs by use of XCL1 represents a novel and promising method for inducing cytotoxic T cell reponses. Targeting the right dendritic cell subset in the right cutaneous compartment via PLEASE® laser microporation is a promising approach for immunotherapy also e.g. against allergies and pathogens. Citation Format: Dorothea Terhorst, Dorothea Terhorst, Even Fossum, Bjarne Bogen, Sandrine Henri, Bernard Malissen. Laser-assisted intradermal delivery of XCL1-specific fusion vaccines induces potent antitumor response. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr A54.
Richard A Kroczek - One of the best experts on this subject based on the ideXlab platform.
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rat cytomegalovirus encoded γ chemokine vXCL1 is a highly adapted species specific agonist for rat xcr1 positive dendritic cells
Journal of Cell Science, 2019Co-Authors: Agnieszka Bauer, Hans W Mages, Julia Madela, Christian Berg, Viktorija Daugvilaite, Stephanie Gurka, Richard A Kroczek, Mette M Rosenkilde, Sebastian VoigtAbstract:Dendritic cells (DCs) expressing the chemokine receptor XCR1 are specialized in antigen cross-presentation to control infections with intracellular pathogens. XCR1-positive (XCR1+) DCs are attracted by XCL1, a γ-chemokine secreted by activated CD8+ T cells and natural killer cells. Rat cytomegalovirus (RCMV) is the only virus known to encode a viral XCL1 analog (vXCL1) that competes for XCR1 binding with the endogenous chemokine. Here we show that vXCL1 from two different RCMV strains, as well as endogenous rat XCL1 (rXCL1) bind to and induce chemotaxis exclusively in rat XCR1+ DCs. Whereas rXCL1 activates the XCR1 Gi signaling pathway in rats and humans, both of the vXCL1s function as species-specific agonists for rat XCR1. In addition, we demonstrate constitutive internalization of XCR1 in XCR1-transfected HEK293A cells and in splenic XCR1+ DCs. This internalization was independent of β-arrestin 1 and 2 and was enhanced after binding of vXCL1 and rXCL1; however, vXCL1 appeared to be a stronger agonist. These findings suggest a decreased surface expression of XCR1 during DC cultivation at 37°C, and subsequent impairment of chemotactic activity and XCR1+ DC function.
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structure function relationship of XCL1 used for in vivo targeting of antigen into xcr1 dendritic cells
Frontiers in Immunology, 2018Co-Authors: Arthur L Kroczek, Evelyn Hartung, Hans W Mages, Stephanie Gurka, Sebastian Voigt, Martina Becker, Nele Reeg, Christian Freund, Richard A KroczekAbstract:XCL1 is the ligand for XCR1, a chemokine receptor uniquely expressed on cross-presenting dendritic cells (DC) in mouse and man. We are interested in establishing therapeutic vaccines based on XCL1-mediated targeting of peptides or proteins into these DC. Therefore, we have functionally analyzed various XCL1 domains in highly relevant settings in vitro and in vivo. Murine XCL1 fused to ovalbumin (XCL1-OVA) was compared to an N-terminal deletion variant lacking the first seven N-terminal amino acids and to several C-terminal (deletion) variants. Binding studies with primary XCR1+ DC revealed that the N-terminal region stabilizes the binding of XCL1 to its receptor, as is known for other chemokines. Deviating from the established paradigm for chemokines, the N-terminus does not contain critical elements for inducing chemotaxis. On the contrary, this region appears to limit the chemotactic action of XCL1 at higher concentrations. A participation of the XCL1 C-terminus in receptor binding or chemotaxis could be excluded in a series of experiments. Binding studies with apoptotic and necrotic XCR1-negative cells suggested a second function for XCL1: marking of stressed cells for uptake into cross-presenting DC. In vivo studies using CD8+ T cell proliferation and cytotoxicity as readouts confirmed the critical role of the N-terminus for antigen targeting, and excluded any involvement of the C-terminus in the uptake, processing, and presentation of the fused OVA antigen. Together, these studies provide basic data on the function of the various XCL1 domains as well as relevant information on XCL1 as an antigen carrier in therapeutic vaccines.
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cytomegalovirus expresses the chemokine homologue vXCL1 capable of attracting xcr1 cd4 dendritic cells
Journal of Virology, 2014Co-Authors: Henriette Geyer, Evelyn Hartung, Hans W Mages, Richard A Kroczek, Christoph Weise, Robert Belužic, Oliver Vugrek, Stipan Jonjic, Sebastian VoigtAbstract:Cytomegaloviruses (CMV) have developed various strategies to escape the immune system of the host. One strategy involves the expression of virus-encoded chemokines to modulate the host chemokine network. We have identified in the English isolate of rat CMV (murid herpesvirus 8 [MuHV8]) an open reading frame encoding a protein homologous to the chemokine XCL1, the only known C chemokine. Viral XCL1 (vXCL1), a glycosylated protein of 96 amino acids, can be detected 13 h postinfection in the supernatant of MuHV8-infected rat embryo fibroblasts. vXCL1 exclusively binds to CD4(-) rat dendritic cells (DC), a subset of DC that express the corresponding chemokine receptor XCR1. Like endogenous rat XCL1, vXCL1 selectively chemoattracts XCR1(+) CD4(-) DC. Since XCR1(+) DC in mice and humans have been shown to excel in antigen cross-presentation and thus in the induction of cytotoxic CD8(+) T lymphocytes, the virus has apparently hijacked this gene to subvert cytotoxic immune responses. The biology of vXCL1 offers an interesting opportunity to study the role of XCL1 and XCR1(+) DC in the cross-presentation of viral antigens.
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the role of xcr1 and its ligand XCL1 in antigen cross presentation by murine and human dendritic cells
Frontiers in Immunology, 2012Co-Authors: Richard A Kroczek, Volker HennAbstract:Recently, the chemokine receptor XCR1 has been found to be exclusively expressed on a subset of DC known to be involved in antigen cross-presentation. This review aims to summarize the known biology of the XCR1 receptor and its chemokine ligand XCL1, both in the mouse and the human. Further, any involvement of this receptor-ligand pair in antigen uptake, cross-presentation, and induction of innate and adaptive cytotoxic immunity is explored. The concept of antigen delivery to DC via the XCR1 receptor is discussed as a vaccination strategy for selective induction of cytotoxic immunity against certain pathogens or tumors.
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the role of xcr1 and its ligand XCL1 in antigen cross presentation by murine and human dendritic cells
Frontiers in Immunology, 2012Co-Authors: Richard A Kroczek, Volker HennAbstract:Recently, the chemokine receptor XCR1 has been found to be exclusively expressed on a subset of dendritic cell (DC) known to be involved in antigen cross-presentation. This review aims to summarize the known biology of the XCR1 receptor and its chemokine ligand XCL1, both in the mouse and the human. Further, any involvement of this receptor-ligand pair in antigen uptake, cross-presentation, and induction of innate and adaptive cytotoxic immunity is explored. The concept of antigen delivery to DC via the XCR1 receptor is discussed as a vaccination strategy for selective induction of cytotoxic immunity against certain pathogens or tumors.
Susann Kowal - One of the best experts on this subject based on the ideXlab platform.
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the systemic exercise released chemokine lymphotactin XCL1 modulates in vitro adult hippocampal precursor cell proliferation and neuronal differentiation
Scientific Reports, 2019Co-Authors: Odette Leiter, Stefanie N Bernas, Suse Seidemann, Rupert W Overall, Cindy Horenburg, Susann KowalAbstract:Physical exercise has well-established anti-inflammatory effects, with neuro-immunological crosstalk being proposed as a mechanism underlying the beneficial effects of exercise on brain health. Here, we used physical exercise, a strong positive modulator of adult hippocampal neurogenesis, as a model to identify immune molecules that are secreted into the blood stream, which could potentially mediate this process. Proteomic profiling of mouse plasma showed that levels of the chemokine lymphotactin (XCL1) were elevated after four days of running. We found that XCL1 treatment of primary cells isolated from both the dentate gyrus and the subventricular zone of the adult mice led to an increase in the number of neurospheres and neuronal differentiation in neurospheres derived from the dentate gyrus. In contrast, primary dentate gyrus cells isolated from XCL1 knockout mice formed fewer neurospheres and exhibited a reduced neuronal differentiation potential. XCL1 supplementation in a dentate gyrus-derived neural precursor cell line promoted neuronal differentiation and resulted in lower cell motility and a reduced number of cells in the S phase of the cell cycle. This work suggests an additional function of the chemokine XCL1 in the brain and underpins the complexity of neuro-immune interactions that contribute to the regulation of adult hippocampal neurogenesis.
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The systemic exercise-released chemokine lymphotactin/XCL1 modulates in vitro adult hippocampal precursor cell proliferation and neuronal differentiation.
Scientific reports, 2019Co-Authors: Odette Leiter, Stefanie N Bernas, Suse Seidemann, Rupert W Overall, Cindy Horenburg, Susann Kowal, Gerd Kempermann, Tara L. WalkerAbstract:Physical exercise has well-established anti-inflammatory effects, with neuro-immunological crosstalk being proposed as a mechanism underlying the beneficial effects of exercise on brain health. Here, we used physical exercise, a strong positive modulator of adult hippocampal neurogenesis, as a model to identify immune molecules that are secreted into the blood stream, which could potentially mediate this process. Proteomic profiling of mouse plasma showed that levels of the chemokine lymphotactin (XCL1) were elevated after four days of running. We found that XCL1 treatment of primary cells isolated from both the dentate gyrus and the subventricular zone of the adult mice led to an increase in the number of neurospheres and neuronal differentiation in neurospheres derived from the dentate gyrus. In contrast, primary dentate gyrus cells isolated from XCL1 knockout mice formed fewer neurospheres and exhibited a reduced neuronal differentiation potential. XCL1 supplementation in a dentate gyrus-derived neural precursor cell line promoted neuronal differentiation and resulted in lower cell motility and a reduced number of cells in the S phase of the cell cycle. This work suggests an additional function of the chemokine XCL1 in the brain and underpins the complexity of neuro-immune interactions that contribute to the regulation of adult hippocampal neurogenesis.
