title: Abrogation of donor T-cell IL-21 signaling leads to tissue-specific modulation of immunity and separation of GVHD from GVL.
abstract: IL-21 is a proinflammatory cytokine produced by Th17 cells. Abrogation of IL-21 signaling has recently been shown to reduce GVHD while retaining graft-versus-leukemia/lymphoma (GVL) responses. However, the mechanisms by which IL-21 may lead to a separation of GVHD and GVL remain incompletely understood. In a murine MHC-mismatched BM transplantation model, we observed that IL-21 receptor knockout (IL-21R KO) donor T cells mediate decreased systemic and gastrointestinal GVHD in recipients of a transplant. This reduction in GVHD was associated with expansion of transplanted donor regulatory T cells and with tissue-specific modulation of Th-cell function. IL-21R KO and wild-type donor T cells showed equivalent alloactivation, but IL-21R KO T cells showed decreased infiltration and inflammatory cytokine production within the mesenteric lymph nodes. However, Th-cell cytokine production was maintained peripherally, and IL-21R KO T cells mediated equivalent immunity against A20 and P815 hematopoietic tumors. In summary, abrogation of IL-21 signaling in donor T cells leads to tissue-specific modulation of immunity, such that gastrointestinal GVHD is reduced, but peripheral T-cell function and GVL capacity are retained. IL-21 is thus an exciting target for therapeutic intervention and improvement of clinical transplantation outcomes.
authors: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors: Alan M
authors: AM
authors: Hanash
authors: Lucy W
authors: LW
authors: Kappel
authors: Nury L
authors: NL
authors: Yim
authors: Rebecca A
authors: RA
authors: Nejat
authors: Gabrielle L
authors: GL
authors: Goldberg
authors: Odette M
authors: OM
authors: Smith
authors: Uttam K
authors: UK
authors: Rao
authors: Lindsay
authors: L
authors: Dykstra
authors: Il-Kang
authors: IK
authors: Na
authors: Amanda M
authors: AM
authors: Holland
authors: Jarrod A
authors: JA
authors: Dudakov
authors: Chen
authors: C
authors: Liu
authors: George F
authors: GF
authors: Murphy
authors: Warren J
authors: WJ
authors: Leonard
authors: Glenn
authors: G
authors: Heller
authors: Marcel R M
authors: MR
authors: van den Brink
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