title: TGF-β upregulates CD70 expression and induces exhaustion of effector memory T cells in B-cell non-Hodgkin's lymphoma.
abstract: Transforming growth factor beta (TGF-β) has an important role in mediating T-cell suppression in B-cell non-Hodgkin lymphoma (NHL). However, the underlying mechanism responsible for TGF-β-mediated inhibition of effector memory T (Tm) cells is largely unknown. As reported here, we show that exhaustion is a major mechanism by which TGF-β inhibits Tm cells, and TGF-β mediated exhaustion is associated with upregulation of CD70. We found that TGF-β upregulates CD70 expression on effector Tm cells while it preferentially induces Foxp3 expression in naive T cells. CD70 induction by TGF-β is Smad3-dependent and involves IL-2/Stat5 signaling. CD70+ T cells account for TGF-β-induced exhaustion of effector Tm cells. Both TGF-β-induced and preexisting intratumoral CD70+ effector Tm cells from B-cell NHL have an exhausted phenotype and express higher levels of PD-1 and TIM-3 compared with CD70- T cells. Signaling transduction, proliferation and cytokine production are profoundly decreased in these cells, and they are highly susceptible to apoptosis. Clinically, intratumoral CD70-expressing T cells are prevalent in follicular B-cell lymphoma (FL) biopsy specimens, and increased numbers of intratumoral CD70+ T cells correlate with an inferior patient outcome. These findings confirm TGF-β-mediated effector Tm cell exhaustion as an important mechanism of immune suppression in B-cell NHL.
authors.affiliation: Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Z-Z
authors.initials: ZZ
authors.lastname: Yang
authors.affiliation: Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Grote
authors.affiliation: Department of Hematology, Tongji Hospital, Tongji University, Shanghai, China.
authors.forename: B
authors.initials: B
authors.lastname: Xiu
authors.affiliation: Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Ziesmer
authors.affiliation: Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: T L
authors.initials: TL
authors.lastname: Price-Troska
authors.affiliation: Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: L S
authors.initials: LS
authors.lastname: Hodge
authors.affiliation: Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: D M
authors.initials: DM
authors.lastname: Yates
authors.affiliation: Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Novak
authors.affiliation: Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Ansell
mesh_terms: D017209:Apoptosis; D053282:CD27 Ligand / Q000235:genetics / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D000072597:Hepatitis A Virus Cellular Receptor 2; D006801:Humans; D007156:Immunologic Memory; D007376:Interleukin-2 / Q000502:physiology; D016393:Lymphoma, B-Cell / Q000276:immunology*; D008565:Membrane Proteins / Q000032:analysis; D061026:Programmed Cell Death 1 Receptor / Q000032:analysis; D050799:STAT5 Transcription Factor / Q000502:physiology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000502:physiology
chemical_list: D053282:CD27 Ligand; C505771:CD70 protein, human; C448908:HAVCR2 protein, human; D000072597:Hepatitis A Virus Cellular Receptor 2; D007376:Interleukin-2; D008565:Membrane Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D050799:STAT5 Transcription Factor; D016212:Transforming Growth Factor beta; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7