MMP-independent role of TIMP-1 at the blood brain barrier during viral encephalomyelitis

Savarin, Carine; Bergmann, Cornelia C.; Hinton, David R.; Stohlman, Stephen A.

Infection of the CNS (central nervous system) with a sublethal neurotropic coronavirus (JHMV) induces a vigorous inflammatory response. CD4(+) and CD8(+) T cells are essential to control infectious virus but at the cost of tissue damage. An enigma in understanding the contribution of T cell subsets in pathogenesis resides in their distinct migration pattern across the BBB (blood brain barrier). CD4(+) T cells transiently accumulate within the perivascular space, whereas CD8(+) T cells migrate directly into the CNS parenchyma. As MMPs (matrix metalloproteinases) facilitate migration across the glia limitans, specific expression of the TIMP (tissue inhibitor of MMPs)-1 by CD4(+) T cells present in the perivascular cuffs suggested that TIMP-1 is responsible for stalling CD4(+) T cell migration into the CNS parenchyma. Using TIMP-1 deficient mice, the present data demonstrate an increase rather than a decrease in CD4(+) T cell accumulation within the perivascular space during JHMV infection. Whereas virus control was not affected by perivascular retention of CD4(+) T cells, disease severity was decreased and associated with reduced IFNγ (interferon γ) production. Moreover, decreased CD4(+) T cell recruitment into the CNS parenchyma of TIMP-1 deficient mice was not associated with impaired T cell recruiting chemokines or MMP expression, and no compensation by other TIMP molecules was identified. These data suggest an MMP-independent role of TIMP-1 in regulating CD4(+) T cell access into the CNS parenchyma during acute JHMV encephalitis.