title: Memory Stem T Cells in Autoimmune Disease: High Frequency of Circulating CD8+ Memory Stem Cells in Acquired Aplastic Anemia.
abstract: Memory stem T cells (TSCMs) constitute a long-lived, self-renewing lymphocyte population essential for the maintenance of functional immunity. Hallmarks of autoimmune disease pathogenesis are abnormal CD4(+) and CD8(+) T cell activation. We investigated the TSCM subset in 55, 34, 43, and 5 patients with acquired aplastic anemia (AA), autoimmune uveitis, systemic lupus erythematosus, and sickle cell disease, respectively, as well as in 41 age-matched healthy controls. CD8(+) TSCM frequency was significantly increased in AA compared with healthy controls. An increased CD8(+) TSCM frequency at diagnosis was associated with responsiveness to immunosuppressive therapy, and an elevated CD8(+) TSCM population after immunosuppressive therapy correlated with treatment failure or relapse in AA patients. IFN-γ and IL-2 production was significantly increased in various CD8(+) and CD4(+) T cell subsets in AA patients, including CD8(+) and CD4(+) TSCMs. CD8(+) TSCM frequency was also increased in patients with autoimmune uveitis or sickle cell disease. A positive correlation between CD4(+) and CD8(+) TSCM frequencies was found in AA, autoimmune uveitis, and systemic lupus erythematosus. Evaluation of PD-1, CD160, and CD244 expression revealed that TSCMs were less exhausted compared with other types of memory T cells. Our results suggest that the CD8(+) TSCM subset is a novel biomarker and a potential therapeutic target for AA.
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892; kohei.hosokawa@nih.gov.
authors.forename: Kohei
authors.identifier: http://orcid.org/0000-0002-3423-1523
authors.initials: K
authors.lastname: Hosokawa
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Pawel
authors.initials: P
authors.lastname: Muranski
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Xingmin
authors.initials: X
authors.lastname: Feng
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Townsley
authors.affiliation: Clinical Immunology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Baoying
authors.initials: B
authors.lastname: Liu
authors.affiliation: Clinical Immunology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Jared
authors.initials: J
authors.lastname: Knickelbein
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Keyvan
authors.initials: K
authors.lastname: Keyvanfar
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Bogdan
authors.initials: B
authors.lastname: Dumitriu
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Sawa
authors.initials: S
authors.lastname: Ito
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Sachiko
authors.identifier: http://orcid.org/0000-0003-1035-3662
authors.initials: S
authors.lastname: Kajigaya
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: James G
authors.initials: JG
authors.lastname: Taylor
authors.affiliation: Systemic Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892; and.
authors.forename: Mariana J
authors.initials: MJ
authors.lastname: Kaplan
authors.affiliation: Clinical Immunology Section, National Eye Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Robert B
authors.initials: RB
authors.lastname: Nussenblatt
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: A John
authors.initials: AJ
authors.lastname: Barrett
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: John
authors.identifier: http://orcid.org/0000-0002-6456-9752
authors.initials: J
authors.lastname: O'Shea
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;
authors.forename: Neal S
authors.initials: NS
authors.lastname: Young
mesh_terms: D000328:Adult; D000368:Aged; D000741:Anemia, Aplastic / Q000097:blood / Q000175:diagnosis / Q000276:immunology* / Q000628:therapy*; D000755:Anemia, Sickle Cell / Q000175:diagnosis / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology; D015415:Biomarkers / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000145:classification / Q000276:immunology*; D005260:Female; D006801:Humans; D007156:Immunologic Memory; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008180:Lupus Erythematosus, Systemic / Q000175:diagnosis / Q000276:immunology; D008213:Lymphocyte Activation; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D054504:Precursor Cells, T-Lymphoid / Q000276:immunology*; D012008:Recurrence; D016176:T-Lymphocyte Subsets; D017211:Treatment Failure; D014605:Uveitis / Q000175:diagnosis / Q000276:immunology
chemical_list: D015415:Biomarkers; D007376:Interleukin-2; D007371:Interferon-gamma