title: 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 CD4(dim)CD8(bright) T cells. We evaluated the role of CD4(dim)CD8(bright) 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 CD4(dim)CD8(bright)) were found in NSG-huPBMC mouse brain within 2 wk of infection. Wnts secreted from astrocytes induced CD4(dim)CD8(bright) T cells by 2-fold in vitro. Injection of highly purified CD8 single positive T cells into mouse brain induced CD4(dim)CD8(bright) T cells by 10-fold, which were proliferative and exhibited a terminally differentiated effector memory phenotype. Brain CD4(dim)CD8(bright) 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 CD4(dim)CD8(bright) 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 CD4(dim)CD8(bright) T cells, likely through a Wnt signaling-dependent manner, and that these cells are associated with potent anti-HIV control in the CNS. Thus, CD4(dim)CD8(bright) T cells are capable of HIV control in the CNS and may offer protection against HIV-associated neurocognitive disorders.
authors.affiliation: Department of Immunology and Microbiology, Rush University Medical Center, Chicago, IL 60612.
authors.forename: Maureen H
authors.identifier: http://orcid.org/0000-0002-1530-1557
authors.initials: MH
authors.lastname: Richards
authors.affiliation: Department of Immunology and Microbiology, Rush University Medical Center, Chicago, IL 60612.
authors.forename: Srinivas D
authors.initials: SD
authors.lastname: Narasipura
authors.affiliation: Department of Immunology and Microbiology, Rush University Medical Center, Chicago, IL 60612.
authors.forename: Melanie S
authors.initials: MS
authors.lastname: Seaton
authors.affiliation: Department of Immunology and Microbiology, Rush University Medical Center, Chicago, IL 60612.
authors.forename: Victoria
authors.initials: V
authors.lastname: Lutgen
authors.affiliation: Department of Immunology and Microbiology, Rush University Medical Center, Chicago, IL 60612 Lena_Al-Harthi@rush.edu.
authors.forename: Lena
authors.initials: L
authors.lastname: Al-Harthi
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000276:immunology* / Q000821:virology; D015704:CD4 Antigens / Q000378:metabolism*; D016827:CD8 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D064593:Heterografts; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000637:transplantation; D008213:Lymphocyte Activation / Q000276:immunology; D052118:Lysosomal-Associated Membrane Protein 1 / Q000378:metabolism; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D013154:Spleen / Q000166:cytology; D060449:Wnt Signaling Pathway / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; C507942:Il2rg protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D052118:Lysosomal-Associated Membrane Protein 1; D052119:Lysosomal-Associated Membrane Protein 2