Blockade of individual Notch ligands and receptors controls graft-versus-host disease

Abstract

Graft-versus-host disease (GVHD) is

The Notch Signaling Pathway Controls Short-Lived Effector CD8+ T Cell Differentiation but Is Dispensable for Memory Generation

“…However, Notch3 and Notch4 mRNA were not increased (24,39) (data not shown); thus, the deletion of Notch1 and Notch2 genes should completely abrogate Notch signaling in CD8 + T cells. To elucidate the role of the Notch signaling pathway during in vivo CD8 + T cell response, Notch1 and Notch2 expression was specifically abrogated in mature CD8 + T cells using Notch1 fl/fl Notch2 fl/fl -E8I-Cre +/2 mice (referred as Notch1/2-deficient mice or D/D through the manuscript).…”

The histone methyltransferase Ezh2 is a crucial epigenetic regulator of allogeneic T-cell responses mediating graft-versus-host disease

“…42,44 As a result, inhibition of Notch signaling reduces GVHD but preserves potent GVL. 42,45 Other studies also suggest that inhibition of PKC-u, which is critical for expansion of alloreactive T cells, reduces GVHD and preserves GVL. 43 These observations support the idea that elimination of leukemic cells requires either less alloreactivity or fewer alloreactive effector T cells than induction of lethal GVHD.…”

Programming of donor T cells using allogeneic δ-like ligand 4–positive dendritic cells to reduce GVHD in mice

“…[12][13][14][15][16] Notch receptors interact with Notch ligands of the d-like and Jagged families, [17][18][19] triggering the release of intracellular Notch (ICN) that activates Notch target genes. [17][18][19] Inhibiting pan-Notch signaling in donor T cells reduced their production of interferon g (IFN-g) and interleukin-17 (IL-17).…”