title: Expansion of dysfunctional Tim-3-expressing effector memory CD8+ T cells during simian immunodeficiency virus infection in rhesus macaques.
abstract: The T cell Ig- and mucin domain-containing molecule-3 (Tim-3) negative immune checkpoint receptor demarcates functionally exhausted CD8(+) T cells arising from chronic stimulation in viral infections like HIV. Tim-3 blockade leads to improved antiviral CD8(+) T cell responses in vitro and, therefore, represents a novel intervention strategy to restore T cell function in vivo and protect from disease progression. However, the Tim-3 pathway in the physiologically relevant rhesus macaque SIV model of AIDS remains uncharacterized. We report that Tim-3(+)CD8(+) T cell frequencies are significantly increased in lymph nodes, but not in peripheral blood, in SIV-infected animals. Tim-3(+)PD-1(+)CD8(+) T cells are similarly increased during SIV infection and positively correlate with SIV plasma viremia. Tim-3 expression was found primarily on effector memory CD8(+) T cells in all tissues examined. Tim-3(+)CD8(+) T cells have lower Ki-67 content and minimal cytokine responses to SIV compared with Tim-3(-)CD8(+) T cells. During acute-phase SIV replication, Tim-3 expression peaked on SIV-specific CD8(+) T cells by 2 wk postinfection and then rapidly diminished, irrespective of mutational escape of cognate Ag, suggesting non-TCR-driven mechanisms for Tim-3 expression. Thus, rhesus Tim-3 in SIV infection partially mimics human Tim-3 in HIV infection and may serve as a novel model for targeted studies focused on rejuvenating HIV-specific CD8(+) T cell responses.
authors.affiliation: Department of Tropical Medicine, Hawaii Center for AIDS, John A. Burns School of Medicine, University of Hawaii, Manoa, HI 96813; Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan;
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Fujita
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006; Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006;
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Burwitz
authors.affiliation: Department of Tropical Medicine, Hawaii Center for AIDS, John A. Burns School of Medicine, University of Hawaii, Manoa, HI 96813;
authors.forename: Glen M
authors.initials: GM
authors.lastname: Chew
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006; Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006;
authors.forename: Jason S
authors.initials: JS
authors.lastname: Reed
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006; Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006;
authors.forename: Reesab
authors.initials: R
authors.lastname: Pathak
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006; Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006;
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Seger
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; and.
authors.forename: Kiera L
authors.initials: KL
authors.lastname: Clayton
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; and.
authors.forename: James M
authors.initials: JM
authors.lastname: Rini
authors.affiliation: Department of Immunology, University of Toronto, Toronto, Ontario M5S 1A8, Canada; and.
authors.forename: Mario A
authors.initials: MA
authors.lastname: Ostrowski
authors.affiliation: Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan;
authors.forename: Naoto
authors.initials: N
authors.lastname: Ishii
authors.affiliation: Division of Immunology, Tulane National Primate Research Center, Covington, LA 70433.
authors.forename: Marcelo J
authors.initials: MJ
authors.lastname: Kuroda
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006; Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006;
authors.forename: Scott G
authors.initials: SG
authors.lastname: Hansen
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health and Science University, Beaverton, OR 97006; Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR 97006; lndhlovu@hawaii.edu sacha@ohsu.edu.
authors.forename: Jonah B
authors.initials: JB
authors.lastname: Sacha
authors.affiliation: Department of Tropical Medicine, Hawaii Center for AIDS, John A. Burns School of Medicine, University of Hawaii, Manoa, HI 96813; lndhlovu@hawaii.edu sacha@ohsu.edu.
authors.forename: Lishomwa C
authors.initials: LC
authors.lastname: Ndhlovu
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000628:therapy; D000595:Amino Acid Sequence; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007156:Immunologic Memory; D007167:Immunotherapy / Q000379:methods*; D008253:Macaca mulatta; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000628:therapy; D015302:Simian Immunodeficiency Virus / Q000502:physiology*; D019562:Viral Load; D014779:Virus Replication
chemical_list: C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; D061026:Programmed Cell Death 1 Receptor