title: Phosphatidylinositol 3-kinase-independent signaling pathways contribute to ICOS-mediated T cell costimulation in acute graft-versus-host disease in mice.
abstract: We and others have previously shown that ICOS plays an important role in inducing acute graft-versus-host disease (GVHD) in murine models of allogeneic bone marrow transplantation. ICOS potentiates TCR-mediated PI3K activation and intracellular calcium mobilization. However, ICOS signal transduction pathways involved in GVHD remain unknown. In this study, we examined the contribution of ICOS-PI3K signaling in the pathogenic potential of T cells using a knock-in mouse strain, ICOS-YF, which selectively lost the ability to activate PI3K. We found that when total T cells were used as alloreactive T cells, ICOS-YF T cells caused less severe GVHD compared with ICOS wild-type T cells, but they induced much more aggressive disease than ICOS knockout T cells. This intermediate level of pathogenic capacity of ICOS-YF T cells was correlated with similar levels of IFN-γ-producing CD8 T cells that developed in the recipients of ICOS-WT or ICOS-YF T cells. We further evaluated the role of ICOS-PI3K signaling in CD4 versus CD8 T cell compartment using GVHD models that are exclusively driven by CD4 or CD8 T cells. Remarkably, ICOS-YF CD8 T cells caused disease similar to ICOS wild-type CD8 T cells, whereas ICOS-YF CD4 T cells behaved very similarly to their ICOS knockout counterparts. Consistent with their in vivo pathogenic potential, CD8 T cells responded to ICOS ligation in vitro by PI3K-independent calcium flux, T cell activation, and proliferation. Thus, in acute GVHD in mice, CD4 T cells heavily rely on ICOS-PI3K signaling pathways; in contrast, CD8 T cells can use PI3K-independent ICOS signaling pathways, possibly through calcium.
authors.affiliation: Department of Hematology, Xiangya Hospital Central South University, Changsha, Hunan 41008, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Jessica
authors.initials: J
authors.lastname: Heinrichs
authors.forename: Julien
authors.initials: J
authors.lastname: Leconte
authors.forename: Kelley
authors.initials: K
authors.lastname: Haarberg
authors.forename: Kenrick
authors.initials: K
authors.lastname: Semple
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Mathieu
authors.initials: M
authors.lastname: Gigoux
authors.forename: Mara
authors.initials: M
authors.lastname: Kornete
authors.forename: Ciriaco A
authors.initials: CA
authors.lastname: Piccirillo
authors.forename: Woong-Kyung
authors.initials: WK
authors.lastname: Suh
authors.forename: Xue-Zhong
authors.initials: XZ
authors.lastname: Yu
mesh_terms: D000208:Acute Disease; D000818:Animals; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D006086:Graft vs Host Disease / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D060889:Inducible T-Cell Co-Stimulator Protein / Q000172:deficiency / Q000502:physiology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058539:Phosphatidylinositol 3-Kinase / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism
chemical_list: C556694:Icos protein, mouse; D060889:Inducible T-Cell Co-Stimulator Protein; D058539:Phosphatidylinositol 3-Kinase