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 Peripheral Blood Mononuclear Cells (PBMCs) (NSG-huPBMC). All three T cell populations (CD4 single positive, CD8 single positive, and CD4dimCD8bright) were found in NSG-huPBMC mice brain within 2 weeks 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.

Intradermal injection of a Tat Oyi-based therapeutic HIV vaccine reduces of 1.5 log copies/mL the HIV RNA rebound median and no HIV DNA rebound following cART interruption in a phase I/II randomized controlled clinical trial

“…The blood–brain barrier appears to be damaged in HIV infected patients, and extracellular Tat may be involved in this process [ 33 ]. This damage may be due to CTLs that are present in the CNS in the mouse model [ 34 ]. This recent discovery does not fit well with the role of sanctuary that the CNS is thought by some to play for HIV infected cells.…”

HIV and drug abuse mediate astrocyte senescence in a β‐catenin‐dependent manner leading to neuronal toxicity

“…To determine whether astrocyte senescence occurs in vivo , we used IL‐2rγc‐/‐ (NSG) mice reconstituted with human PBLs (huPBLs) and infected with HIV BaL by i.p, as described (Richards et al ., ). Three weeks postinfection, the mice were sacrificed and the brains were analyzed for astrocyte senescence.…”

“…These experiments were performed as described (Richards et al ., ). Six‐ to eight‐week old NSG mice were injected with 2 × 10 7 human PBMCs by intraperitoneal injection (i.p.).…”

CD32 is enriched on CD4dimCD8bright T cells

“…Based on these counts and past clinical records, patients were defined as elite controllers (EC) (undetectable viral loads for >5 years), long term non-progressors (LTNP) (high viral load, CD4 > 500 cells/μL), combination antiretroviral therapy (cART) adherent (viral load <40 copies/mL), and cART non-adherent/ treatment naïve (viremic) (viral load >10,000 copies/mL, CD4 count <500 cells/μL). PBMCs were isolated using ficoll-hypaque density gradient centrifugation [11].…”

“…CD4 and CD8 expression on mature T cells is thought to be mutually exclusive. However, there is extensive body of literature demonstrating that mature CD8 + T cells, upon activation, upregulate CD4 de novo on their surface [1][2][3][4][5][6][7][8][9][10][11][12][13]. These cells have been termed CD4 dim CD8 bright T cells because while the intensity of the CD8 molecule is similar to that of single positive CD8 + T cells, the CD4 molecule expression is lower than that of a single positive CD4 T cell.…”