Non-pathogenic tissue-resident CD8(+) T cells uniquely accumulate in the brains of lupus-prone mice

Severe lupus often includes psychiatric and neurological sequelae, although the cellular contributors to CNS disease remain poorly defined. Using intravascular staining to discriminate tissue-localized from blood-borne cells, we find substantial accumulation of CD8(+) T cells relative to other lymphocytes in brain tissue, which correlates with lupus disease and limited neuropathology. This is in contrast to all other affected organs, where infiltrating CD4(+) cells are predominant. Brain-infiltrating CD8(+) T cells represent an activated subset of those found in the periphery, having a resident-memory phenotype (CD69(+)CD122(−)PD1(+)CD44(+)CD62L(−)) and expressing adhesion molecules (VLA-4(+)LFA-1(+)) complementary to activated brain endothelium. Remarkably, infiltrating CD8(+) T cells do not cause tissue damage in lupus-prone mice, as genetic ablation of these cells via β2 m deficiency does not reverse neuropathology, but exacerbates disease both in the brain and globally despite decreased serum IgG levels. Thus, lupus-associated inflammation disrupts the blood-brain barrier in a discriminating way biased in favor of non-pathogenic CD8(+) T cells relative to other infiltrating leukocytes, perhaps preventing further tissue damage in such a sensitive organ.