Absence of inducible costimulator on alloreactive T cells reduces graft versus host disease and induces Th2 deviation.
Inducible costimulator (ICOS) is expressed on activated and memory T cells and is involved in the regulation of cytokine production. We studied the role of ICOS on alloreactive T cells in graft versus host disease (GVHD) and determined that ICOS expression was up-regulated on alloreactive T cells in recipients of an allogeneic hematopoietic stem cell transplantation (allo-HSCT) with GVHD. We compared ICOS-/- T cells with wild-type (WT) T cells in 2 GVHD models. In both models, recipients of ICOS-/- T cells demonstrated significantly less GVHD morbidity and mortality, which was associated with less intestinal and hepatic GVHD but increased cutaneous GVHD. In addition, recipients of ICOS-/- donor T cells displayed a slight decrease in graft versus leukemia (GVL) activity. Further analysis of alloreactive ICOS-/- T cells showed no defect in activation, proliferation, cytotoxicity, and target organ infiltration. Recipients of ICOS-/- T cells had decreased serum levels of interferon-gamma (IFN-gamma), while interleukin-4 (IL-4) and IL-10 levels were increased, suggesting that alloreactive ICOS-/- T cells are skewed toward T helper-2 (Th2) differentiation. These data suggest a novel role for ICOS in the regulation of Th1/Th2 development of activated T cells. In conclusion, alloreactive ICOS-/- donor T cells induce less GVHD due to a Th2 immune deviation while GVL activity is slightly diminished.
Hubbard
Vanessa M
VM
Department of Medicine and ImmunologyMemorial Sloan-Kettering Cancer Center, Kettering 406D, Mailbox 111, 1275 York Ave, New York, NY 10021, USA.
Eng
Jeffrey M
JM
Ramirez-Montagut
Teresa
T
Tjoe
Kartono H
KH
Muriglan
Stephanie J
SJ
Kochman
Adam A
AA
Terwey
Theis H
TH
Willis
Lucy M
LM
Schiro
Rafaella
R
Heller
Glen
G
Murphy
George F
GF
Liu
Chen
C
Alpdogan
Onder
O
van den Brink
Marcel R M
MR
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000502:physiology*; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D060889:Inducible T-Cell Co-Stimulator Protein; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D015854:Up-Regulation
D000945:Antigens, Differentiation, T-Lymphocyte; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein