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CNS inflammation

CNS inflammation. Charo, I.F. & Ransohoff, R.M. The many roles of chemokines and chemokine receptors in inflammation. N. Engl. J. Med. 354, 610–621 (2006). CCR6-KO mice do not develop EAE. In CCR6 - KO mice MOG- reactive Th17 and Th1 cells are primed but do not migrate into the CNS.

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CNS inflammation

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  1. CNS inflammation Charo, I.F. & Ransohoff, R.M. The many roles of chemokines and chemokine receptors in inflammation. N. Engl. J. Med. 354, 610–621 (2006)

  2. CCR6-KO mice do not develop EAE

  3. In CCR6-KO mice MOG-reactive Th17 and Th1 cells are primed but do not migrate into the CNS

  4. CCR6 is not required for Th-17 priming in vitro

  5. …and for proliferation/differentiation in vivo • CCR6 is selectively upregulated in mouse Th17 cells, but not required for priming

  6. Transfer of wildtype 2D2 T cells reconstitutes disease susceptibility in CCR6-KO mice

  7. Reconstitution with other Knock-outs

  8. … but on day 20 the T cells in the CNS are endogenous CCR6-KO Th1 and Th17

  9. CCR6-KO T cells enter the CNS during active EAE 2D2 = green, CD45 = red

  10. CCR6 is not required for rolling and adhesion to inflamed endothelial cells of CNS parenchyma

  11. CCR6 requirement under steady state conditionsand at early time points during EAE

  12. Routes for leukocyte migration into the CNS Ransohoff, R.M., Kivisakk, P. & Kidd, G. Three or more routes for leukocyte migration into the central nervous system. Nat. Rev. Immunol. 3, 569–581 (2003)

  13. Is the choroid plexus the port of entry of CCR6+ Th17 cells? Engelhardt, B. & Ransohoff, R.M. The ins and outs of T-lymphocyte trafficking to the CNS: anatomical sites and molecular mechanisms. Trends Immunol. 26, 485–495 (2005)

  14. The CCR6 ligand CCL20 is highly expressedin epithelial cells of the mouse choroid plexus

  15. In CCR6-KO mice immunized with MOG+CFAlymphocytes are trapped in the choroid plexus

  16. The CCR6 ligand CCL20 (MIP-3β, LARC) is constitutively expressed in human choroid epithelium

  17. Constitutive and inflammatory routes of entry into the CNS: a two step model of EAE pathogenesis • CCR6-mediated Th17 cell entry into the CSF via the choroid plexus. • Th17 dissemination via the CSF to the subarachnoid space and antigen recognition and local activation of the blood brain barrier. • (2) CCR6-independent T cell entry through locally activated parenchimalvenules of the blood brain barrier.

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