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.

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.

CNS immune privilege: hiding in plain sight.

Central nervous system (CNS) immune privilege is an experimentally defined phenomenon. Tissues that are rapidly rejected by the immune system when grafted in sites, such as the skin, show prolonged survival when grafted into the CNS. Initially, CNS immune privilege was construed as CNS isolation from the immune system by the blood-brain barrier (BBB), the lack of draining lymphatics, and the apparent immunoincompetence of microglia, the resident CNS macrophage. CNS autoimmunity and neurodegeneration were presumed automatic consequences of immune cell encounter with CNS antigens. Recent data have dramatically altered this viewpoint by revealing that the CNS is neither isolated nor passive in its interactions with the immune system. Peripheral immune cells can cross the intact BBB, CNS neurons and glia actively regulate macrophage and lymphocyte responses, and microglia are immunocompetent but differ from other macrophage/dendritic cells in their ability to direct neuroprotective lymphocyte responses. This newer view of CNS immune privilege is opening the door for therapies designed to harness autoreactive lymphocyte responses and also implies (i) that CNS autoimmune diseases (i.e. multiple sclerosis) may result as much from neuronal and/or glial dysfunction as from immune system dysfunctions and (ii) that the severe neuronal and glial dysfunction associated with neurodegenerative disorders (i.e. Alzheimer's disease) likely alters CNS-specific regulation of lymphocyte responses affecting the utility of immune-based therapies (i.e. vaccines).