Opposing effects of ICOS on graft-versus-host disease mediated by CD4 and CD8 T cells.
ICOS, a CD28 family member expressed on activated CD4(+) and CD8(+) T cells, plays important roles in T cell activation and effector function. Here we studied the role of ICOS in graft-vs-host disease (GVHD) mediated by CD4(+) or CD8(+) T cells in allogeneic bone marrow transplantation. In comparison of wild-type and ICOS-deficient T cells, we found that recipients of ICOS(-/-) CD4(+) T cells exhibited significantly less GVHD morbidity and delayed mortality. ICOS(-/-) CD4(+) T cells had no defect in expansion, but expressed significantly less Fas ligand and produced significantly lower levels of IFN-gamma and TNF-alpha. Thus, ICOS(-/-) CD4(+) T cells were impaired in effector functions that lead to GVHD. In contrast, recipients of ICOS(-/-) CD8(+) T cells exhibited significantly enhanced GVHD morbidity and accelerated mortality. In the absence of ICOS signaling, either using ICOS-deficient donors or ICOS ligand-deficient recipients, the levels of expansion and Tc1 cytokine production of CD8(+) T cells were significantly increased. The level of expansion was inversely correlated with the level of apoptosis, suggesting that increased ability of ICOS(-/-) CD8(+) T cells to induce GVHD resulted from the enhanced survival and expansion of those cells. Our findings indicate that ICOS has paradoxical effects on the regulation of alloreactive CD4(+) and CD8(+) T cells in GVHD.
Yu
Xue-Zhong
XZ
Immunology and Blood and Marrow Transplantation Programs, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA. YuXZ@moffitt.usf.edu
Liang
Yaming
Y
Nurieva
Roza I
RI
Guo
Fei
F
Anasetti
Claudio
C
Dong
Chen
C
D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000502:physiology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002455:Cell Division / Q000276:immunology; D049109:Cell Proliferation; D002478:Cells, Cultured; D006086:Graft vs Host Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D006131:Growth Inhibitors / Q000235:genetics / Q000502:physiology*; D060889:Inducible T-Cell Co-Stimulator Protein; D007519:Isoantigens / Q000008:administration & dosage / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*
D000945:Antigens, Differentiation, T-Lymphocyte; D006131:Growth Inhibitors; C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D007519:Isoantigens