Migration of CD8+ T Cells into the Central Nervous System Gives Rise to Highly Potent Anti-HIV CD4dimCD8bright T Cells in a Wnt Signaling–Dependent Manner

Abstract

The role of CD8+ T cells in HIV control in the brain and the consequences of such control are unclear. Approximately 3% of peripheral CD8+ T cells dimly express CD4 on their surface. This population is known as CD4dimCD8bright T cells. We evaluated the role of CD4dimCD8bright and CD8 single positive T cells in HIV-infected brain using NOD/SCID/IL-2rcγ−/− mice reconstituted with human PBMCs (NSG-huPBMC). All three T cell populations (CD4 single positive, CD8 single positive, and CD4dimCD8bright) were found in NSG-huPBMC mouse brain within 2 wk of infection. Wnts secreted from astrocytes induced CD4dimCD8bright T cells by 2-fold in vitro. Injection of highly purified CD8 single positive T cells into mouse brain induced CD4dimCD8bright T cells by 10-fold, which were proliferative and exhibited a terminally differentiated effector memory phenotype. Brain CD4dimCD8bright T cells from HIV-infected mice exhibited anti-HIV–specific responses, as demonstrated by induction of CD107ab post exposure to HIV peptide–loaded targets. Further, higher frequency of CD4dimCD8bright T cells (R = −0.62; p ≤ 0.001), but not CD8 single positive T cells (R = −0.24; p ≤ 0.27), negatively correlated with HIV gag mRNA transcripts in HIV-infected NSG-huPBMC brain. Together, these studies indicate that single positive CD8+ T cells entering the CNS during HIV infection can give rise to CD4dimCD8bright T cells, likely through a Wnt signaling–dependent manner, and that these cells are associated with potent anti-HIV control in the CNS. Thus, CD4dimCD8bright T cells are capable of HIV control in the CNS and may offer protection against HIV-associated neurocognitive disorders.