Interferon regulatory factor 4 plays a pivotal role in the development of aGVHD-associated colitis

Oncoimmunology. 2023 Dec 27;13(1):2296712. doi: 10.1080/2162402X.2023.2296712. eCollection 2024.

Abstract

Interferon regulatory factor 4 (IRF4) is a master transcription factor that regulates T helper cell (Th) differentiation. It interacts with the Basic leucine zipper transcription factor, ATF-like (BATF), depletion of which in CD4+ T cells abrogates acute graft-versus-host disease (aGVHD)-induced colitis. Here, we investigated the immune-regulatory role of Irf4 in a mouse model of MHC-mismatched bone marrow transplantation. We found that recipients of allogenic Irf4-/- CD4+ T cells developed less GVHD-related symptoms. Transcriptome analysis of re-isolated donor Irf4-/- CD4+ T helper (Th) cells, revealed gene expression profiles consistent with loss of effector T helper cell signatures and enrichment of a regulatory T cell (Treg) gene expression signature. In line with these findings, we observed a high expression of the transcription factor BTB and CNC homolog 2; (BACH2) in Irf4-/- T cells, which is associated with the formation of Treg cells and suppression of Th subset differentiation. We also found an association between BACH2 expression and Treg differentiation in patients with intestinal GVHD. Finally, our results indicate that IRF4 and BACH2 act as counterparts in Th cell polarization and immune homeostasis during GVHD. In conclusion, targeting the BACH2/IRF4-axis could help to develop novel therapeutic approaches against GVHD.

Keywords: Acute GVHD; BACH2; IRF4; T helper cells.

MeSH terms

  • Animals
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • Colitis* / chemically induced
  • Colitis* / genetics
  • Graft vs Host Disease* / genetics
  • Graft vs Host Disease* / metabolism
  • Humans
  • Interferon Regulatory Factors / genetics
  • Interferon Regulatory Factors / metabolism
  • Mice
  • T-Lymphocytes, Regulatory / metabolism

Substances

  • Interferon Regulatory Factors
  • Basic-Leucine Zipper Transcription Factors

Grants and funding

This work was supported by the LOEWE Center for Cell and Gene Therapy (E.U., J.T.F.), Frankfurt, funded by the Hessian Ministry of Higher Education, Research and the Arts, Germany (III L 4- 518/17.004), by the Max-Eder Research Program of the German Cancer Aid (E.U.), by the Adolf Messer Foundation (E.U.) and the Wilhelm Sander Foundation (Grant 2017.020.002 to E.H.). J.C. was supported by the IRTG of the Collaborative Research Center CRC 1292 (TP12 to E.U.) by the Deutsche Forschungsgemeinschaft (DFG). R.Z. was supported by the DFG (SFB 850 C6, SFB1160, ZE 872/4-2, TRR167), the Deutsche Krebshilfe (grant number 70113473), and the Jose-Carreras Leukemia foundation grant number DJCLS 01 R/2019.