title: PD-1 and Tim-3 pathways are associated with regulatory CD8+ T-cell function in decidua and maintenance of normal pregnancy.
abstract: CD8+ T cells are critical in the balance between fetal tolerance and antiviral immunity. T-cell immunoglobulin mucin-3 (Tim-3) and programmed cell death-1 (PD-1) are important negative immune regulatory molecules involved in viral persistence and tumor metastasis. Here, we demonstrate that Tim-3+PD-1+CD8+ T cells from decidua greatly outnumbered those from peripheral blood during human early pregnancy. Co-culture of trophoblasts with CD8+ T cells upregulated PD-1+ and/or Tim-3+ immune cells. Furthermore, the population of CD8+ T cells co-expressing PD-1 and Tim-3 was enriched within the intermediate memory subset in decidua. This population exhibited high proliferative activity and Th2-type cytokine producing capacity. Blockade of Tim-3 and PD-1 resulted in decreased in vitro proliferation and Th2-type cytokine production while increased trophoblast killing and IFN-γ producing capacities of CD8+ T cells. Pregnant CBA/J females challenged with Tim-3 and/or PD-1 blocking antibodies were more susceptible to fetal loss, which was associated with CD8+ T-cell dysfunction. Importantly, the number and function of Tim-3+PD-1+CD8+ T cells in decidua were significantly impaired in miscarriage. These findings underline the important roles of Tim-3 and PD-1 pathways in regulating decidual CD8+ T-cell function and maintaining normal pregnancy.
authors.affiliation: 1] Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China [2] Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China.
authors.forename: S-C
authors.initials: SC
authors.lastname: Wang
authors.affiliation: 1] Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China [2] Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China.
authors.forename: Y-H
authors.initials: YH
authors.lastname: Li
authors.affiliation: 1] Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China [2] Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China.
authors.forename: H-L
authors.initials: HL
authors.lastname: Piao
authors.affiliation: Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
authors.forename: X-W
authors.initials: XW
authors.lastname: Hong
authors.affiliation: 1] Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China [2] Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China.
authors.forename: D
authors.initials: D
authors.lastname: Zhang
authors.affiliation: 1] Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China [2] Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China.
authors.forename: Y-Y
authors.initials: YY
authors.lastname: Xu
authors.affiliation: 1] Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China [2] Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Tao
authors.affiliation: 1] Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China [2] Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: 1] Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China [2] Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China.
authors.forename: M-M
authors.initials: MM
authors.lastname: Yuan
authors.affiliation: 1] Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China [2] Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China.
authors.forename: D-J
authors.initials: DJ
authors.lastname: Li
authors.affiliation: 1] Laboratory for Reproductive Immunology, Hospital and Institute of Obstetrics and Gynecology, Fudan University Shanghai Medical College, Shanghai 200011, China [2] Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Shanghai 200011, China.
authors.forename: M-R
authors.initials: MR
authors.lastname: Du
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D018920:Coculture Techniques; D003656:Decidua / Q000276:immunology / Q000378:metabolism*; D005260:Female; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D011247:Pregnancy / Q000097:blood / Q000276:immunology / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D014327:Trophoblasts / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation
chemical_list: C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D008565:Membrane Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor