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Blood. 2011 Jan 6;117(1):299-308. doi: 10.1182/blood-2010-03-271940. Epub 2010 Sep 24.

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

Author information

1
Bone Marrow Transplantation Program, University of Michigan, Ann Arbor, MI 48109, USA. yizha@med.umich.edu

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.

PMID:
20870902
PMCID:
PMC3037751
DOI:
10.1182/blood-2010-03-271940
[Indexed for MEDLINE]
Free PMC Article
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