Ablation of IRF4 in donor T cells eliminates GVHD while partially preserving GVT in experimental bone marrow transplantation

Abstract

Abstract Objective We discovered that the transcription factor IRF4 governs T cell function in heart transplantation (Immunity 47:1114). Here, using a bone marrow (BM) transplantation model, we studied the role of IRF4 in regulating T cell function in graft-vs-host disease (GVHD) and graft-vs-tumor (GVT). Methods 9 Gy irradiated Balb/c recipients were i.v. injected: 1) with 5 × 106 T cell-depleted CD45.1+ B6 BM cells; 2) with or without 0.1 × 106 Balb/c A20-luciferase lymphoma cells; and 3) with or without 1 × 106 CD45.2+ wild type (WT), Irf4−/−, or Irf4−/−Foxp3sf/Y (Treg-deficient Irf4−/−) B6 donor T cells. GVHD, GVT, survival, and donor T cell states were determined. Results In the absence of A20 infusion, all recipients without T cell transfer (n=10), or transferred with Irf4−/− (n=10) or Irf4−/−Foxp3sf/Y (n=5) donor T cells survived long-term (>60 days post BM transplantation). Recipients transferred with WT donor T cells had developed lethal GVHD [mean survival time (MST) = 9.5±2 days; n =8]. Among A20 infused groups, recipients without T cell transfer died due to lymphoma progression (MST=22±2.80 days; n =15). Transfer of Irf4−/− donor T cells led to a moderate GVT effect and significantly prolonged survival (MST=33.4 ± 11.22 days; n =15; p<0.001 vs no T cell). Transferred WT donor T cells exerted potent GVT activity but caused lethal GVHD (12.56 ± 6.02 days; n = 18). Mechanistically, Irf4−/− donor T cells developed into effector T cells, but barely infiltrated into GVHD tissues and were prone to apoptosis. Conclusions IRF4 ablation in donor T cells eliminates GVHD in a Treg independent manner while partially preserving GVT. This reveals the possibility to separate GVHD and GVT effects by modulating transcription factors in T cells.