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 Toxoplasmainfected nontransgenic 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+ Tlymphocytes outside the CNS and (b) by facilitating CD4+ T-cell migration into parenchymal sites following pathogenic insults to the CNS.

The Microtubule-Associated Protein Lis1 Regulates T Lymphocyte Homeostasis and Differentiation

“…To address this question, we labeled FACS sort-purified naïve T cells with the division-tracking dye CFSE prior to adoptive transfer into sub-lethally irradiated congenic hosts or culture in cytokine conditions in vitro (IL-7 alone for CD8 + T cells and IL-7 plus CCL21 for CD4 + T cells) that have been shown to mimic cytokine-induced homeostatic proliferation in vivo (22, 23). Unlike control T cells, Lis1-deficient T cells failed to undergo homeostatic proliferation in vivo in sub-lethally irradiated wild-type mice at 5 days post-transfer (Fig.…”

Transcriptome Analysis of Mouse Brain Infected with Toxoplasma gondii

“…Microglia generate pro-and antiinflammatory cytokines and chemokines following T. gondii infection (52)(53)(54)(55). In addition to microglia, astrocytes can also inhibit parasite replication upon activation (56).…”

Role of Chemokines and Trafficking of Immune Cells in Parasitic Infections

“…Both CCL21 and CCL19 are upregulated in the brain during infection and linear strands of CCL21 can be observed within the brain parenchyma associated with migrating CD8+ T cells [15, 144]. In addition, CCL21 is required for efficient CD4+ T cell migration from extraparenchymal sites into the brain parenchyma [145] (Figure 2C). This was demonstrated in plt/plt mice (deficient in CCL19 and CCL21-ser) and transgenic GFAP-CCL21 mice (where CCL21 is constitutively over-expressed under the astrocyte specific promoter, GFAP).…”

“…This was demonstrated in plt/plt mice (deficient in CCL19 and CCL21-ser) and transgenic GFAP-CCL21 mice (where CCL21 is constitutively over-expressed under the astrocyte specific promoter, GFAP). In wild type mice chronically infected with T. gondii , immune infiltrates can be observed in the perivascular spaces and meninges, in addition to the tissue parenchyma [145]. In mice lacking CCL19/CCL21, significantly higher numbers of CD4+ T cells are recruited to the brain.…”

“…However, these cells accumulate in the extraparenchymal spaces. In contrast, mice overexpressing CCL21 displayed little accumulation of CD4+ T cells in extraparenchymal spaces and instead were found dispersed throughout the brain instead of focused in the frontal cortex where T. gondii primarily resides [145]. …”