Thymic CCL2 influences induction of T-cell tolerance

Cédile, Oriane; Løbner, Morten; Toft-Hansen, Henrik; Frank, Ida; Włodarczyk, Agnieszka; Irla, Magali; Owens, Trevor

doi:10.1016/j.jaut.2014.07.004

Cited by 19 publications

(24 citation statements)

References 59 publications

(61 reference statements)

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“…Although CCL2-deficient mice are reported to be resistant to EAE [15], transgenic overexpression of CCL2 in the CNS was reported to prevent EAE [9]. We have published that transgenic mice overexpressing CCL2 show pronounced impairment of T cell development and are consequently resistant to EAE [5]. Touil et al [36] showed that treatment of mice with neutralizing antibody against CCL2 reversed the suppressive effect of peripherally administered poly I:C on EAE.…”

Section: Discussionmentioning

confidence: 99%

Induction of endogenous Type I interferon within the central nervous system plays a protective role in experimental autoimmune encephalomyelitis

et al. 2015

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The Type I interferons (IFN), beta (IFN-β) and the alpha family (IFN-α), act through a common receptor and have anti-inflammatory effects. IFN-β is used to treat multiple sclerosis (MS) and is effective against experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Mice with EAE show elevated levels of Type I IFNs in the central nervous system (CNS), suggesting a role for endogenous Type I IFN during inflammation. However, the therapeutic benefit of Type I IFN produced in the CNS remains to be established. The aim of this study was to examine whether experimentally induced CNS-endogenous Type I IFN influences EAE. Using IFN-β reporter mice, we showed that direct administration of polyinosinic–polycytidylic acid (poly I:C), a potent inducer of IFN-β, into the cerebrospinal fluid induced increased leukocyte numbers and transient upregulation of IFN-β in CD45/CD11b-positive cells located in the meninges and choroid plexus, as well as enhanced IFN-β expression by parenchymal microglial cells. Intrathecal injection of poly I:C to mice showing first symptoms of EAE substantially increased the normal disease-associated expression of IFN-α, IFN-β, interferon regulatory factor-7 and IL-10 in CNS, and disease worsening was prevented for as long as IFN-α/β was expressed. In contrast, there was no therapeutic effect on EAE in poly I:C-treated IFN receptor-deficient mice. IFN-dependent microglial and astrocyte response included production of the chemokine CXCL10. These results show that Type I IFN induced within the CNS can play a protective role in EAE and highlight the role of endogenous type I IFN in mediating neuroprotection.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-015-1418-z) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Induction of endogenous Type I interferon within the central nervous system plays a protective role in experimental autoimmune encephalomyelitis

et al. 2015

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“…CCL2‐deficient or CCR2‐RFP/RFP mice 8–10 weeks old were anesthetized with an intraperitoneal injection of ketamine (Ketalar ® , 100 mg/kg of body weight; Pfizer, Glostrup, Denmark) and xylazine (Rompun ® , 10 mg/kg of body weight; Bayer, Glostrup, Denmark). Eight microliters of replication‐defective adenovirus [10 7 infectious units (ifu)] in sterile PBS was injected into the cisterna magna using a 30G stainless‐steel needle curved (40°) at 2.5 mm from the tip . After the injection, mice received a subcutaneous injection of buprenorphine (Temgesic ® , 0.1 mg/kg of body weight; Indivior UK Limited, Glostrup, Denmark).…”

Section: Methodsmentioning

confidence: 99%

CCL2 recruits T cells into the brain in a CCR2‐independent manner

Cédile

Włodarczyk

Owens

2017

APMIS

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CCL2 is a chemokine that can be induced during neuroinflammation to recruit immune cells, but its role in the central nervous system (CNS) is unclear. Our aim was to better understand its role. We induced CCL2 in CNS of naive CCL2-deficient mice using intrathecally administered replication-defective adenovirus and examined cell infiltration by flow cytometry. CCL2 expression induced pronounced and unexpected recruitment of regulatory and IFNγ-producing T cells to CNS from blood, possibly related to defective egress of monocytes from CCL2-deficient bone marrow. Infiltration also occurred in mice lacking CCR2, a receptor for CCL2. Expression of another receptor for CCL2, CCR4, and CXCR3, a receptor for CXCL10, which was also induced, were both increased in CCL2-treated CNS. CCR4 was expressed by neurons and astrocytes as well as CD4 T cells, and CXCR3 was expressed by CD4 and CD8 T cells. Chemokine-recruited T cells did not lead to CNS pathology. Our findings show a role for CCL2 in recruitment of CD4 T cells to the CNS and show that redundancy among chemokine receptors ensures optimal response.

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“…In homeostatic state and lymphopenic hosts, these mature T lymphocytes exert different functions in the thymus: maintenance of the medullary epithelial cells survival, contribution to positive selection through their MHC molecules, participation to negative selection through the antigens they present, or killing of the antigen-presenting cells they recognized [18][19][20] . Thymic CCL2 expression was also recently described to contribute to antigen tolerance through the recruitment of thymic SIRPα + and plasmacytoid dendritic cells [21,22] . Therefore, our current investigations are now focused on identifying mechanisms by which the CCL2/CCR2 signaling pathway could impair the thymocytes differentiation in the course of AML.…”

Section: Research Highlightmentioning

confidence: 96%

Macrophages and myeloid derived suppressor cells-independent dysregulation of thymopoiesis by CCL2 in acute myeloid leukemia

Driss

Brinster

2015

Macrophage

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In cancer-affected patients and experimental mouse models, the CCL2 chemokine is well documented to directly stimulate the proliferation and migration of tumor cells. It also attracts type 2 macrophages and myeloid derived suppressor cells that abrogate intra-tumor T-cell responses and facilitate cancer cells growth and metastasis. Accumulation of CCL2 has been found in the sera of patients suffering from acute myeloid leukemia (AML), however, its functions in disease development remain to be determined. Using an AML experimental mouse model, we have recently shown increased levels of CCL2 in the sera and thymi of mice. CCL2 blockade in vivo resulted in prolonged leukemic mice survival, lower tumor burden and enhanced anti-leukemic responses. In this work, we highlighted a surprising role of CCL2 during AML which affects thymic function in the absence of macrophages and myeloid derived suppressor cells recruitment. To cite this article: Virginie Driss, et al. Macrophages and myeloid derived suppressor cells-independent dysregulation of thymopoiesis by CCL2 in acute myeloid leukemia. Macrophage 2015; 2: e902.

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Thymic CCL2 influences induction of T-cell tolerance

Cited by 19 publications

References 59 publications

Induction of endogenous Type I interferon within the central nervous system plays a protective role in experimental autoimmune encephalomyelitis

Induction of endogenous Type I interferon within the central nervous system plays a protective role in experimental autoimmune encephalomyelitis

CCL2 recruits T cells into the brain in a CCR2‐independent manner

Macrophages and myeloid derived suppressor cells-independent dysregulation of thymopoiesis by CCL2 in acute myeloid leukemia

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