Interferon regulatory factor 4 deficiency in CD8⁺ T cells abrogates terminal effector differentiation and promotes transplant acceptance

Allogeneic CD8⁺ cytotoxic T cells play an essential role in rejecting transplanted allografts, but how their effector function is regulated on a transcriptional level remains unclear. Herein, we investigate the role of interferon regulatory factor 4 (IRF4) in controlling CD8⁺ T-cell function in response to transplant. B6.Rag1^−/− mice were adoptively transferred with CD8⁺ T cells isolated from either Irf4^fl/flCd4-Cre (T-cell-specific Irf4-deficient) or Irf4^fl/fl control mice, followed by BALB/c skin transplantation. Recipients that received Irf4-deficient CD8⁺ T cells permanently accepted the skin allografts, whereas recipients that received control CD8⁺ T cells acutely rejected the transplanted skins. Mechanistically, compared with the transferred control CD8⁺ T cells in B6.Rag1^−/− recipients, the transferred Irf4-deficient CD8⁺ T cells lost the capacity to differentiate into CD127⁻KLRG1⁺ terminal effector cells, barely produced effector cytokines and cytotoxic molecules (e.g. IL-2, IFN-γ, TNF-α, granzyme A and granzyme B), and displayed defect in proliferative capacity, evident by their decreased Ki67 expression and lower frequencies. Moreover, the transferred Irf4-deficient CD8⁺ T cells displayed low expression of transcription factors ID2 and T-bet that govern the terminal effector T-cell programmes, and high expression of transcription factor TCF1 that maintains the naïve-memory T-cell programmes. Hence, IRF4 deficiency in CD8⁺ T cells abrogates their terminal effector differentiation and promotes transplant acceptance. These findings suggest that targeting IRF4 expression represents an attractive and promising therapeutic approach for inducing transplant acceptance.