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

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

Acknowledgments

The authors thank Bushra Rais, Katja Stein, Franziska Ganß, Silvia Lindlar and Petra Schoen for their excellent technical assistance, Emilia Salzmann-Manrique und Martin Hutter for support concerning the bioinformatics, Tobias Bopp and Virginie Lecaudey for critical discussion of the manuscript as well as Andreas Jarisch and Jan Soerensen for the provision of GVHD therapeutics.

Furthermore, we thank Andreas Beilhack from Würzburg for providing transgenic mice and discussing data. We thank Boris Brill and all animal care takers as well as Petra Dinse from the Georg Speyer Haus/FCI Frankfurt for support in mouse experiments, including colonoscopy and histological analysis.

Disclosure statement

The authors declare no conflict of interest related to this work. E.U. acts as medical advisor of Phialogics and received research funding from Gilead and Bristol-Myers Squibb. R.Z. received honorarium for participation in scientific meetings and advisory boards from Incyte, Mallinckrodt and Novartis.

Author contributions

J.T.F., J.C., D.Y.S.F., S.G. and S.H. performed experiments, J.T.F., J.C., D.Y.S.F., N.V., S.G., E.M., S.H. and D.H. analyzed and interpreted data. E.H., S.G. and E.M. provided human colon RNA samples, performed analyses related to human colon biopsies and helped with the interpretation and critical discussion of the results. M.L., D.S., S.S., R.S., H.B. and A.G.C. provided critical reagents and mice. D.H., E.H. and R.Z. helped to design experiments and discussed the results, A.G.C. and A.K. gave critical advice and helped with the interpretation and critical discussion of the results.

E.U. designed and directed the study; J.C., J.T.F, and E.U. wrote the manuscript with contributions of all authors.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/2162402X.2023.2296712.

Additional information

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.