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

• Published in: Blood 2011-07, Vol.118 (2), p.446-455
• Main Authors: Hanash, Alan M., Kappel, Lucy W., Yim, Nury L., Nejat, Rebecca A., Goldberg, Gabrielle L., Smith, Odette M., Rao, Uttam K., Dykstra, Lindsay, Na, Il-Kang, Holland, Amanda M., Dudakov, Jarrod A., Liu, Chen, Murphy, George F., Leonard, Warren J., Heller, Glenn, van den Brink, Marcel R.M.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Gene Knockdown Techniques; Graft vs Host Disease - genetics; Graft vs Host Disease - immunology; Graft vs Host Disease - metabolism; Graft vs Leukemia Effect - genetics; Hematologic and hematopoietic diseases; 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; Medical sciences; 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; Transplantation Immunology
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2010-07-294785

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.