Work

Abrogation of Donor T Cell IL-21 Signaling Leads to Tissue-Specific Modulation of Immunity and Separation of GVHD From GVL

Year: 2011

Type: article

Abstract: Interleukin 21 (IL-21) is a pro-inflammatory cytokine produced by Th17 helper T cells, and abrogation of IL-21 signaling has recently been shown to reduce GVHD while retaining GVL. However, mechanisms by which IL-21 may lead to a separation of GVHD and GVL are incompletely understood. To characterize its effect on GVH and GVL T cell responses, we compared wild type (WT) and IL-21 receptor knockout (IL-21R KO) donor T cells in a C57BL/6 into BALB/c murine MHC-mismatched bone marrow transplant (BMT) model. Lethally irradiated BMT recipients of IL-21R KO T cells demonstrated decreased GVHD-related morbidity (p < .05) and mortality (p < .01) and decreased histopathologic evidence of GVHD within the small bowel (p < .05). While this reduced GVHD was associated with increased donor regulatory T cells two to three weeks post-BMT (p < .001), transplanting selected T cell subsets indicated that IL-21 signaling in both donor CD4 and CD8 T cells contributed to GVHD mortality (CD4, p < .01; CD8, p < .05), although effects on CD8 T cells occurred only in the presence of CD4s. KO and WT donor T cells demonstrated equivalent alloactivation, as evidenced by proliferation (p < .001), upregulation of CD25 (p < .001), and downregulation of CD62L (p < .01 for CD8 T cells) in allogeneic vs. syngeneic recipients. However, IL-21R KO T cells demonstrated decreased infiltration within the small bowel (p < .05) and mesenteric lymph nodes (MLN; CD8, p < .05; CD4, p < .001), and decreased inflammatory cytokine-producing CD4 T cells within MLN (IFN-γ, p < .01; TNF-α, p < .001). Consistent with this, transplanted IL-21R KO donor T cells demonstrated decreased expression of α4β7 integrin (LPAM, p < .05), a molecule known to be involved in homing of GVHD-mediating donor T cells to the gut. However, in contrast to the reduced inflammatory cytokine-producing CD4 T cells observed in MLN, IL-21R KO helper T cell cytokine production was maintained in spleen and peripheral lymph nodes, and IL-21R KO T cells were able to protect recipient mice from lethality due to A20 lymphoma (p < .001). 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. Targeting IL-21 for therapeutic intervention is an exciting strategy to separate GVHD from GVL, and this novel approach should be considered for clinical investigation to improve transplant outcomes and prevent malignant relapse.

Source: Transplantation and Cellular Therapy

DOI: 10.1016/j.bbmt.2010.12.038