IRF4 controls a core regulatory circuit of T cell dysfunction in transplantation

Abstract T cell dysfunction has emerged as a key event leading to failure in the control of persistent infections and tumors. However, the transcriptional determinants for T cell dysfunction remain unknown. Here we show that IRF4 is a key transcriptional determinant of T cell dysfunction by restraining the dysfunctional differentiation process. We use a heart transplantation model to decipher the molecular basis of T cell dysfunction. Heart allografts survived indefinitely in Irf4-deficient mice. This stable engraftment is due to the progressive establishment of effector T cell dysfunction. Mechanistically, IRF4 represses PD-1, Helios, and other molecules associated with T cell dysfunction. In particular, IRF4 has a profound impact on epigenetic accessibility of PD-1 cis-regulatory elements. In the absence of IRF4, chromatin accessibility as well as binding of Helios at PD-1 cis-regulatory elements are markedly increased in effector T cells, resulting in enhanced expression of PD-1 and T cell dysfunction. Intriguingly, although the dysfunctional state of Irf4-deficient T cells is initially reversible by blockade of PD-1/PD-L1 pathway, it progressively evolves into a “terminal” irreversible state within 30 days post-transplant. Lastly, we revealed that the MEK1/2 inhibitor, trametinib, dramatically decreases IRF4 expression in T cells, abrogates EAE development, and prolongs heart allograft survival. Our results reveal a previously unappreciated aspect of T cell dysfunction, namely the repression of the dysfunctional differentiation of T cells by IRF4. Central control of T cell dysfunction by IRF4 has a significant potential impact on the course of future work in modulating T cell dysfunction