How transplant rejection is regulated on a transcriptional level remains unclear. We found that T cell-specific conditional knockout (cKO) of the transcription factor IRF4 in B6 mice induced long-term Balb/c heart allograft survival (all > 100 days; n=6) without any immunosuppressive therapies. IRF4 repressed PD-1, Helios and other molecules associated with T cell dysfunction; in its absence, chromatin accessibility and binding of Helios at PD-1 cis-regulatory elements were markedly increased, resulting in persistent PD-1 expression and T cell dysfunction. To further define the dysfunctional state of Irf4-deficient T cells, Irf4 cKO mice were transplanted with Balb/c hearts and treated with checkpoint blockade (anti-PD-L1 plus anti-CTLA-4) on days 0, 3, and 5. All heart allografts were rejected on days 7-8 due to checkpoint blockade-mediated reinvigoration of Irf4-deficient T cells. At 30 days after heart grafting, recipients were transplanted again with Balb/c skins. Strikingly, those Irf4 cKO recipients with rejected Balb/c heart allografts still permanently accepted the subsequent Balb/c skins (all >100 days; n=6). These results indicate that checkpoint blockade-reinvigorated alloreactive Irf4-deficient T cells become re-dysfunction within 30 days. We used microarray analysis to compare the gene expression profiles between the adoptively transferred CD45.2⁺ WT and Irf4^−/− alloreactive TCR transgenic TEa cells in CD45.1⁺ mice following heart transplantation and checkpoint blockade. On day 6 post-heart grafting, checkpoint blockade restored the expression levels of the majority of WT TEa cell-expressed genes in Irf4^−/− TEa cells, which explains why checkpoint blockade robustly reverse the initial dysfunction of Irf4-deficient T cells. However, the remaining un-restored genes (Wnt10a, snn, Lmo4) following checkpoint blockade, though minimal in number, may be responsible for the reinvigorated Irf4-deficient T cells to become re-dysfunction. Taken together, IRF4 deletion drives intrinsic T cell dysfunction, and targeting IRF4 represents a potential therapeutic strategy for achieving transplant tolerance.

CITATION INFORMATION: Wu J., Zhang H., Shi X., Xiao X., Fan Y., Xia J., Sciammas R., Li X., Chen W. Ablation of IRF4 Induces Transplant Tolerance by Driving Intrinsic T Cell Dysfunction Am J Transplant. 2017;17 (suppl 3).

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