Notch signaling is a critical regulator of allogeneic CD4+ T-cell responses mediating graft-versus-host disease

Y Zhang, AR Sandy, J Wang, V Radojcic… - Blood, The Journal …, 2011 - ashpublications.org
Y Zhang, AR Sandy, J Wang, V Radojcic, GT Shan, IT Tran, A Friedman, K Kato, S He, S Cui
Blood, The Journal of the American Society of Hematology, 2011ashpublications.org
Graft-versus-host disease (GVHD) remains the major barrier to the success of allogeneic
hematopoietic stem cell transplantation (HSCT). GVHD is caused by donor T cells that
mediate host tissue injury through multiple inflammatory mechanisms. Blockade of individual
effector molecules has limited efficacy in controlling GVHD. Here, we report that Notch
signaling is a potent regulator of T-cell activation, differentiation, and function during acute
GVHD. Inhibition of canonical Notch signaling in donor T cells markedly reduced GVHD …
Abstract
Graft-versus-host disease (GVHD) remains the major barrier to the success of allogeneic hematopoietic stem cell transplantation (HSCT). GVHD is caused by donor T cells that mediate host tissue injury through multiple inflammatory mechanisms. Blockade of individual effector molecules has limited efficacy in controlling GVHD. Here, we report that Notch signaling is a potent regulator of T-cell activation, differentiation, and function during acute GVHD. Inhibition of canonical Notch signaling in donor T cells markedly reduced GVHD severity and mortality in mouse models of allogeneic HSCT. Although Notch-deprived T cells proliferated and expanded in response to alloantigens in vivo, their ability to produce interleukin-2 and inflammatory cytokines was defective, and both CD4+ and CD8+ T cells failed to up-regulate selected effector molecules. Notch inhibition decreased the accumulation of alloreactive T cells in the intestine, a key GVHD target organ. However, Notch-deprived alloreactive CD4+ T cells retained significant cytotoxic potential and antileukemic activity, leading to improved overall survival of the recipients. These results identify Notch as a novel essential regulator of pathogenic CD4+ T-cell responses during acute GVHD and suggest that Notch signaling in T cells should be investigated as a therapeutic target after allogeneic HSCT.
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