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Early Notch Signals Induce a Pathogenic Molecular Signature during Priming of Alloantigen-Specific Conventional CD4+ T Cells in Graft-versus-Host Disease.
Chung, Jooho; Radojcic, Vedran; Perkey, Eric; Parnell, Timothy J; Niknafs, Yashar; Jin, Xi; Friedman, Ann; Labrecque, Nathalie; Blazar, Bruce R; Brennan, Todd V; Siebel, Christian W; Maillard, Ivan.
Afiliación
  • Chung J; Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109.
  • Radojcic V; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109.
  • Perkey E; Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109.
  • Parnell TJ; Division of Hematology and Hematologic Malignancies, University of Utah, Salt Lake City, UT 84112.
  • Niknafs Y; Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109.
  • Jin X; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109.
  • Friedman A; Huntsman Cancer Institute Bioinformatic Analysis Shared Resource, University of Utah, Salt Lake City, UT 84112.
  • Labrecque N; Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109.
  • Blazar BR; Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109.
  • Brennan TV; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109.
  • Siebel CW; Centre de Recherche Hôpital Maisonneuve-Rosemont, Université de Montréal, Montreal, Quebec H1T 2M4, Canada.
  • Maillard I; Département de Médecine, Université de Montréal, Montreal, Quebec H3T IJ4, Canada.
J Immunol ; 203(2): 557-568, 2019 07 15.
Article en En | MEDLINE | ID: mdl-31182480
Graft-versus-host disease (GVHD) is the most serious complication of allogeneic hematopoietic cell transplantation. Notch signals delivered during the first 48 h after transplantation drive proinflammatory cytokine production in conventional T cells (Tconv) and inhibit the expansion of regulatory T cells (Tregs). Short-term Notch inhibition induces long-term GVHD protection. However, it remains unknown whether Notch blockade blunts GVHD through its effects on Tconv, Tregs, or both and what early Notch-regulated molecular events occur in alloantigen-specific T cells. To address these questions, we engineered T cell grafts to achieve selective Notch blockade in Tconv versus Tregs and evaluated their capacity to trigger GVHD in mice. Notch blockade in Tconv was essential for GVHD protection as GVHD severity was similar in the recipients of wild-type Tconv combined with Notch-deprived versus wild-type Tregs. To identify the impact of Notch signaling on the earliest steps of T cell activation in vivo, we established a new acute GVHD model mediated by clonal alloantigen-specific 4C CD4+ Tconv. Notch-deprived 4C T cells had preserved early steps of activation, IL-2 production, proliferation, and Th cell polarization. In contrast, Notch inhibition dampened IFN-γ and IL-17 production, diminished mTORC1 and ERK1/2 activation, and impaired transcription of a subset of Myc-regulated genes. The distinct Notch-regulated signature had minimal overlap with known Notch targets in T cell leukemia and developing T cells, highlighting the specific impact of Notch signaling in mature T cells. Our findings uncover a unique molecular program associated with the pathogenic effects of Notch in T cells at the earliest stages of GVHD.
Asunto(s)

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Linfocitos T CD4-Positivos / Receptores Notch / Enfermedad Injerto contra Huésped / Isoantígenos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: J Immunol Año: 2019 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Linfocitos T CD4-Positivos / Receptores Notch / Enfermedad Injerto contra Huésped / Isoantígenos Tipo de estudio: Prognostic_studies Límite: Animals Idioma: En Revista: J Immunol Año: 2019 Tipo del documento: Article