C-C chemokine receptor 6–regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE

Reboldi, Andrea; Coisne, Caroline; Baumjohann, Dirk; Benvenuto, Federica; Bottinelli, Denise; Lira, Sérgio A.; Uccelli, Antonio; Lanzavecchia, Antonio; Engelhardt, Britta; Sallusto, Federica

doi:10.1038/ni.1716

Cited by 1,071 publications

(1,063 citation statements)

References 58 publications

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“…It is thought that autoreactive T cells in MS patients are activated in secondary lymphoid organs and then migrate across the blood-brain barrier into the brain (36). This potential transmigration is underlined by our observation that IL-7 induces VLA-4, an important marker for T cell activation and transmigration into the brain by binding to VCAM-1 on activated brain endothelial cells and epithelial cells of the choroid plexus (37). Natalizumab (Tysabri), a blocking monoclonal blocking Ab against VLA-4 is an approved treatment for MS (38).…”

Section: Discussionsupporting

confidence: 51%

The IL-7Rα Pathway Is Quantitatively and Functionally Altered in CD8 T Cells in Multiple Sclerosis

Kreft

Verbraak

Wierenga‐Wolf

et al. 2012

The Journal of Immunology

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The IL-7Rα single nucleotide polymorphism rs6897932 is associated with an increased risk for multiple sclerosis (MS). IL-7Rα is a promising candidate to be involved in autoimmunity, because it regulates T cell homeostasis, proliferation, and antiapoptotic signaling. However, the exact underlying mechanisms in the pathogenesis of MS are poorly understood. We investigated whether CD4 and CD8 lymphocyte subsets differed in IL-7Rα expression and functionality in 78 MS patients compared with 59 healthy controls (HC). A significantly higher frequency of IL-7Rα+ CD8 effector memory (CD8EM) was found in MS. Moreover, IL-7Rα membrane expression was significantly increased in MS in naive and memory CD8 (all p < 0.05) with a similar trend in CD8EM (p = 0.055). No correlation was found between the expression level or frequency of IL-7Rα+CD8+ and rs6897932 risk allele carriership. Upon IL-7 stimulation, MS patients had stronger STAT5 activation in CD8EM compared with HC. IL-7 stimulation had a differential effect on both mRNA and protein expression of granzyme A and granzyme B between MS and HC. Stainings of different lesions in postmortem MS brain material showed expression of IL-7 and CD8+IL-7Rα+ in preactive, but not in active, demyelinating MS lesions, indicating involvement of IL-7Rα+ lymphocytes in lesion development. The intralesional production of IL-7 in combination with the lower threshold for IL-7–induced cytotoxicity in MS may enhance the pathogenicity of these CD8 T cells. This is of special interest in light of the established demyelinating and cytotoxic actions of granzyme A.

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Section: Discussionsupporting

confidence: 51%

The IL-7Rα Pathway Is Quantitatively and Functionally Altered in CD8 T Cells in Multiple Sclerosis

Kreft

Verbraak

Wierenga‐Wolf

et al. 2012

The Journal of Immunology

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“…Finally, in an attempt to determine whether the enrichment in EBV-specific CD8 1 T cells resulted from selective recruitment, we tested CXCR3 and CCR6 chemokine receptor expression on EBVspecific effector cells raised from the blood and CSF of a subset of patients from the three categories. These receptors have been shown to be important mediators for T-cell entry into the CNS [26,27]. There was no differential expression of these two chemokine receptors between early MS and OIND or NIND patients (data not shown).…”

Section: Characterization Of Ebv-specific Effector Cells Raised From mentioning

confidence: 89%

Intrathecal immune responses to EBV in early MS

et al. 2010

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EBV has been consistently associated with MS, but its signature in the CNS has rarely been examined. In this study, we assessed EBV-specific humoral and cellular immune responses in the cerebrospinal fluid (CSF) of patients with early MS, other inflammatory neurological diseases (OIND) and non-inflammatory neurological diseases (NIND). The neurotropic herpesvirus CMV served as a control. Virus-specific humoral immune responses were assessed in 123 consecutive patients and the intrathecal recruitment of virus-specific antibodies was expressed as antibody indexes. Cellular immune responses tested in the blood of 55/123 patients were positive in 46/55. The CD8 1 CTL responses of these 46 patients were assessed in the blood and CSF using a CFSE-based CTL assay. We found that viral capsid antigen and EBV-encoded nuclear antigen-1, but not CMV IgG antibody indexes, were increased in early MS as compared with OIND and NIND patients. There was also intrathecal enrichment in EBV-, but not CMV-specific, CD8 1 CTL in early MS patients. By contrast, OIND and NIND patients did not recruit EBV-nor CMV-specific CD8 1 CTL in the CSF. Our data, showing a high EBV-, but not CMV-specific intrathecal immune response, strengthen the association between EBV and MS, in particular at the onset of the disease.

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“…Naive αβ T cells express a chemokine receptor CCR7, which is important for homeostatic circulation; its expression is down‐regulated during differentiation and the inflammatory chemokine receptor CCR6 is induced on Th17 cells instead. CCR6 + Th17 cells are recruited by CCL20 to cause inflammation, as shown in SKG mice67 and the EAE model 68, 69. On the other hand, a gene array analysis shows that the expression of chemokine receptors such as CCR6, CCR2 and CXCR6 is already up‐regulated in γδ 17 cells during thymic development 34.…”

Section: Migration Of γδ17 Cells To Inflammatory Sitesmentioning

confidence: 99%

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

Akitsu

Iwakura

2018

Immunology

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SummaryInterleukin‐17 (IL‐17) is a pro‐inflammatory cytokine and is involved in the development of many diseases. Recent studies have revealed that IL‐17‐producing γδ T cells (γδ17 cells) in addition to IL‐17‐producing CD4+ T cells [T helper type 17 (Th17) cells] are often the main producers of IL‐17 in mouse models of inflammatory diseases. γδ T cells are functionally committed during intra‐thymic differentiation. γδ thymocytes capable of producing IL‐17, which express the transcription factor retinoic‐acid‐receptor‐related orphan receptor γt and the signature cytokine receptor IL‐23R, leave the thymus, and produce IL‐17 rapidly by the stimulation with IL‐1β and IL‐23 in the periphery. Therefore, γδ17 cells play important roles in the early phase of host defence against pathogens and in inflammatory diseases. γδ T cells that can produce IL‐17 are also increased in the skin of patients with psoriasis and in peripheral blood of patients with ankylosing sclerosis. Indeed, the therapy targeting IL‐17 has been approved or is in clinical trials, and proved to be very efficient to treat psoriasis, psoriatic arthritis and ankylosing sclerosis. In this review, we discuss recent knowledge about the pathophysiological function of γδ17 cells in infection and inflammatory diseases and therapeutic advances targeting IL‐17.

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C-C chemokine receptor 6–regulated entry of TH-17 cells into the CNS through the choroid plexus is required for the initiation of EAE

Cited by 1,071 publications

References 58 publications

The IL-7Rα Pathway Is Quantitatively and Functionally Altered in CD8 T Cells in Multiple Sclerosis

The IL-7Rα Pathway Is Quantitatively and Functionally Altered in CD8 T Cells in Multiple Sclerosis

Intrathecal immune responses to EBV in early MS

Interleukin‐17‐producing γδ T (γδ17) cells in inflammatory diseases

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