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

Blood. 2011 Jul 14;118(2):446-55. doi: 10.1182/blood-2010-07-294785. Epub 2011 May 19.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Gene Knockdown Techniques
  • Graft vs Host Disease / genetics*
  • Graft vs Host Disease / immunology
  • Graft vs Host Disease / metabolism
  • Graft vs Leukemia Effect / genetics*
  • Humans
  • Immunity, Innate / genetics*
  • Immunity, Innate / physiology
  • Interleukin-21 Receptor alpha Subunit / genetics
  • Interleukin-21 Receptor alpha Subunit / metabolism
  • Interleukin-21 Receptor alpha Subunit / physiology
  • Interleukins / genetics
  • Interleukins / metabolism
  • Interleukins / physiology*
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Inbred DBA
  • Mice, Knockout
  • Organ Specificity / genetics
  • Organ Specificity / immunology
  • Signal Transduction / genetics
  • T-Lymphocytes / metabolism*
  • T-Lymphocytes / physiology
  • Tissue Donors*
  • Transplantation Immunology


  • IL21R protein, human
  • Interleukin-21 Receptor alpha Subunit
  • Interleukins
  • interleukin-21