| First Author | Wu J | Year | 2017 |
| Journal | Immunity | Volume | 47 |
| Issue | 6 | Pages | 1114-1128.e6 |
| PubMed ID | 29221730 | Mgi Jnum | J:259428 |
| Mgi Id | MGI:6141950 | Doi | 10.1016/j.immuni.2017.11.003 |
| Citation | Wu J, et al. (2017) Ablation of Transcription Factor IRF4 Promotes Transplant Acceptance by Driving Allogenic CD4(+) T Cell Dysfunction. Immunity 47(6):1114-1128.e6 |
| abstractText | CD4(+) T cells orchestrate immune responses and destruction of allogeneic organ transplants, but how this process is regulated on a transcriptional level remains unclear. Here, we demonstrated that interferon regulatory factor 4 (IRF4) was a key transcriptional determinant controlling T cell responses during transplantation. IRF4 deletion in mice resulted in progressive establishment of CD4(+) T cell dysfunction and long-term allograft survival. Mechanistically, IRF4 repressed PD-1, Helios, and other molecules associated with T cell dysfunction. In the absence of IRF4, chromatin accessibility and binding of Helios at PD-1 cis-regulatory elements were increased, resulting in enhanced PD-1 expression and CD4(+) T cell dysfunction. The dysfunctional state of Irf4-deficient T cells was initially reversible by PD-1 ligand blockade, but it progressively developed into an irreversible state. Hence, IRF4 controls a core regulatory circuit of CD4(+) T cell dysfunction, and targeting IRF4 represents a potential therapeutic strategy for achieving transplant acceptance. |
