title: CNS-derived CCL21 is both sufficient to drive homeostatic CD4+ T cell proliferation and necessary for efficient CD4+ T cell migration into the CNS parenchyma following Toxoplasma gondii infection.
abstract: Injury, infection and autoimmune triggers increase CNS expression of the chemokine CCL21. Outside the CNS, CCL21 contributes to chronic inflammatory disease and autoimmunity by three mechanisms: recruitment of lymphocytes into injured or infected tissues, organization of inflammatory infiltrates into lymphoid-like structures and promotion of homeostatic CD4+ T-cell proliferation. To test if CCL21 plays the same role in CNS inflammation, we generated transgenic mice with astrocyte-driven expression of CCL21 (GFAP-CCL21 mice). Astrocyte-produced CCL21 was bioavailable and sufficient to support homeostatic CD4+ T-cell proliferation in cervical lymph nodes even in the absence of endogenous CCL19/CCL21. However, lymphocytes and glial-activation were not detected in the brains of uninfected GFAP-CCL21 mice, although CCL21 levels in GFAP-CCL21 brains were higher than levels expressed in inflamed Toxoplasma-infected non-transgenic brains. Following Toxoplasma infection, T-cell extravasation into submeningeal, perivascular and ventricular sites of infected CNS was not CCL21-dependent, occurring even in CCL19/CCL21-deficient mice. However, migration of extravasated CD4+, but not CD8+ T cells from extra-parenchymal CNS sites into the CNS parenchyma was CCL21-dependent. CD4+ T cells preferentially accumulated at perivascular, submeningeal and ventricular spaces in infected CCL21/CCL19-deficient mice. By contrast, greater numbers of CD4+ T cells infiltrated the parenchyma of infected GFAP-CCL21 mice than in wild-type or CCL19/CCL21-deficient mice. Together these data indicate that CCL21 expression within the CNS has the potential to contribute to T cell-mediated CNS pathology via: (a) homeostatic priming of CD4+ T-lymphocytes outside the CNS and (b) by facilitating CD4+ T-cell migration into parenchymal sites following pathogenic insults to the CNS.
authors.affiliation: Roche Ltd., Basel, Switzerland.
authors.forename: Corinne C
authors.initials: CC
authors.lastname: Ploix
authors.forename: Shahani
authors.initials: S
authors.lastname: Noor
authors.forename: Janelle
authors.initials: J
authors.lastname: Crane
authors.forename: Kokoechat
authors.initials: K
authors.lastname: Masek
authors.forename: Whitney
authors.initials: W
authors.lastname: Carter
authors.forename: David D
authors.initials: DD
authors.lastname: Lo
authors.forename: Emma H
authors.initials: EH
authors.lastname: Wilson
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Carson
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000276:immunology / Q000469:parasitology; D015152:Blotting, Northern; D001921:Brain / Q000276:immunology / Q000469:parasitology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000502:physiology; D054421:Chemokine CCL21 / Q000502:physiology*; D002634:Chemotaxis, Leukocyte / Q000276:immunology / Q000502:physiology; D017403:In Situ Hybridization; D008213:Lymphocyte Activation / Q000276:immunology / Q000502:physiology; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000276:immunology / Q000469:parasitology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014122:Toxoplasma / Q000276:immunology*; D016781:Toxoplasmosis, Cerebral / Q000276:immunology*
chemical_list: D054421:Chemokine CCL21