Researchers at the Houston Methodist Research Institute report that they have identified a critical switch that controls T-cell function and dysfunction and have discovered a pathway to target it. Their study (“Ablation of Transcription Factor IRF4 Promotes Transplant Acceptance by Driving Allogenic CD4+ T Cell Dysfunction“) appears in Immunity.
According to Wenhao Chen, Ph.D., a scientist in the Immunobiology and Transplant Science Center at the Institute, what the team discovered is that one of the most critical molecules controlling gene expression in T cells is the transcription factor IRF4, or interferon regulatory factor 4, which is usually only found in the immune system and not expressed in other cells. Dr. Chen says IRF4 is what needs to be targeted to solve the problem of transplant rejection or to develop an autoimmunity cure.
“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 [programmed cell death protein 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,” write the investigators.
“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.”
“We found that IRF4 is an essential regulator of T-cell function,” said Dr. Chen, who is the corresponding author on this paper. “If we delete IRF4 in T cells they become dysfunctional. In doing so, you can solve the issue of autoimmunity and have a potential solution for organ transplant rejection. You need them functional, however, to control infection. If we can find an IRF4 inhibitor, then those issues would be solved. That's big.”
The way they will be able to do this is by only targeting active T cells that have already been exposed to antigens, leaving naïve T cells alone. These naïve T cells produce IRF4 only when needed to fight infections. It's the activated T cells armed with IRF4 that are responsible for organ transplant rejection and autoimmunity. These, he notes, are the ones that are a potential target, thereby leaving other T cells in the immune system still armed against infection.
Their initial results were promising, adds Dr. Chen. By inhibiting IRF4 expression for 30 days, which is the usual timeframe required for transplant patients to remain infection free, the T cells became irreversibly dysfunctional. In practice, this could mean prolonging a patient's ability to tolerate a transplanted organ.
“How to therapeutically inhibit IRF4 is the Nobel-prize winning question,” he continues. “If we can find a way to inhibit IRF4 as desired in activated T cells, then I think most autoimmune diseases and transplant rejection will be solved.”