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Opposing Effects of ICOS on Graft-versus-Host Disease Mediated by CD4 and CD8 T Cells¹

Xue-Zhong Yu^2,*,, Yaming Liang^*, Roza I. Nurieva, Fei Guo^*, Claudio Anasetti^*, and Chen Dong

^* Immunology and Blood and Marrow Transplantation Programs, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612; Department of Interdisciplinary Oncology, University of South Florida, Tampa, FL 33612; and Department of Immunology, MD Anderson Cancer Center, Houston, TX 77030

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- and TNF-. 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.

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