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

Yi Zhang, Ashley R. Sandy, Jina Wang, Vedran Radojcic, Gloria T. Shan, Ivy T. Tran, Ann Friedman, Koji Kato, Shan He, Shuaiying Cui, Elizabeth Hexner, Dale M. Frank, Stephen G. Emerson, Warren S. Pear, Ivan Maillard

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76 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)299-308
Number of pages10
JournalBlood
Volume117
Issue number1
DOIs
Publication statusPublished - Jan 6 2011
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Zhang, Y., Sandy, A. R., Wang, J., Radojcic, V., Shan, G. T., Tran, I. T., Friedman, A., Kato, K., He, S., Cui, S., Hexner, E., Frank, D. M., Emerson, S. G., Pear, W. S., & Maillard, I. (2011). Notch signaling is a critical regulator of allogeneic CD4+ T-cell responses mediating graft-versus-host disease. Blood, 117(1), 299-308. https://doi.org/10.1182/blood-2010-03-271940