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Abrogation of donor T-cell IL-21 signaling leads to tissue-specific modulation of immunity and separation of GVHD from GVL

Item Type:Article
Title:Abrogation of donor T-cell IL-21 signaling leads to tissue-specific modulation of immunity and separation of GVHD from GVL
Creators Name:Hanash, A.M. and Kappel, L.W. and Yim, N.L. and Nejat, R.A. and Goldberg, G.L. and Smith, O.M. and Rao, U.K. and Dykstra, L. and Na, I.K. and Holland, A.M. and Dudakov, J.A. and Liu, C. and Murphy, G.F. and Leonard, W.J. and Heller, G. and van den Brink, M.R.M.
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.
Keywords:Gene Knockdown Techniques, Graft vs Host Disease, Graft vs Leukemia Effect, Innate Immunity, Interleukin-21 Receptor alpha Subunit, Interleukins, Organ Specificity, Signal Transduction, Tissue Donors, T-Lymphocytes, Transplantation Immunology, Tumor-Infiltrating Lymphocytes, Animals, Mice
Publisher:American Society of Hematology
Page Range:446-455
Date:14 July 2011
Official Publication:https://doi.org/10.1182/blood-2010-07-294785
PubMed:View item in PubMed

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