title: T cell-specific notch inhibition blocks graft-versus-host disease by inducing a hyporesponsive program in alloreactive CD4+ and CD8+ T cells.
abstract: Graft-versus-host disease (GVHD) induced by donor-derived T cells remains the major limitation of allogeneic bone marrow transplantation (allo-BMT). We previously reported that the pan-Notch inhibitor dominant-negative form of Mastermind-like 1 (DNMAML) markedly decreased the severity and mortality of acute GVHD mediated by CD4(+) T cells in mice. To elucidate the mechanisms of Notch action in GVHD and its role in CD8(+) T cells, we studied the effects of Notch inhibition in alloreactive CD4(+) and CD8(+) T cells using mouse models of allo-BMT. DNMAML blocked GVHD induced by either CD4(+) or CD8(+) T cells. Both CD4(+) and CD8(+) Notch-deprived T cells had preserved expansion in lymphoid organs of recipients, but profoundly decreased IFN-γ production despite normal T-bet and enhanced Eomesodermin expression. Alloreactive DNMAML T cells exhibited decreased Ras/MAPK and NF-κB activity upon ex vivo restimulation through the TCR. In addition, alloreactive T cells primed in the absence of Notch signaling had increased expression of several negative regulators of T cell activation, including Dgka, Cblb, and Pdcd1. DNMAML expression had modest effects on in vivo proliferation but preserved overall alloreactive T cell expansion while enhancing accumulation of pre-existing natural regulatory T cells. Overall, DNMAML T cells acquired a hyporesponsive phenotype that blocked cytokine production but maintained their expansion in irradiated allo-BMT recipients, as well as their in vivo and ex vivo cytotoxic potential. Our results reveal parallel roles for Notch signaling in alloreactive CD4(+) and CD8(+) T cells that differ from past reports of Notch action and highlight the therapeutic potential of Notch inhibition in GVHD.
authors: Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Ashley R
authors: AR
authors: Sandy
authors: Jooho
authors: J
authors: Chung
authors: Tomomi
authors: T
authors: Toubai
authors: Gloria T
authors: GT
authors: Shan
authors: Ivy T
authors: IT
authors: Tran
authors: Ann
authors: A
authors: Friedman
authors: Timothy S
authors: TS
authors: Blackwell
authors: Pavan
authors: P
authors: Reddy
authors: Philip D
authors: PD
authors: King
authors: Ivan
authors: I
authors: Maillard
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D000098815:T-bet Transcription Factor
chemical_list: D016328:NF-kappa B; D051880:Receptors, Notch; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras)
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