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

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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., Kappel, L.W., Yim, N.L., Nejat, R.A., Goldberg, G.L., Smith, O.M., Rao, U.K., Dykstra, L., Na, I.K., Holland, A.M., Dudakov, J.A., Liu, C., Murphy, G.F., Leonard, W.J., 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
Source:	Blood
ISSN:	0006-4971
Publisher:	American Society of Hematology
Volume:	118
Number:	2
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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