Notch signaling is a critical regulator of allogeneic CD4+ T-cell responses mediating graft-versus-host disease.
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.
Zhang
Yi
Y
Bone Marrow Transplantation Program, University of Michigan, Ann Arbor, MI 48109, USA. yizha@med.umich.edu
Sandy
Ashley R
AR
Wang
Jina
J
Radojcic
Vedran
V
Shan
Gloria T
GT
Tran
Ivy T
IT
Friedman
Ann
A
Kato
Koji
K
He
Shan
S
Cui
Shuaiying
S
Hexner
Elizabeth
E
Frank
Dale M
DM
Emerson
Stephen G
SG
Pear
Warren S
WS
Maillard
Ivan
I
D000818:Animals; D015153:Blotting, Western; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012333:RNA, Messenger / Q000235:genetics; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014184:Transplantation, Homologous; D014916:Whole-Body Irradiation
D016207:Cytokines; D012333:RNA, Messenger; D051880:Receptors, Notch