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

作者：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^*

来源：Blood, 2011, 118(2): 446-455.

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 gastro-intestinal 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 againstA20 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. (Blood. 2011; 118(2): 446-455)

• 出版日期2011-7-14
• 单位NIH