Amongst the Interferon Regulatory Factor (IRF) family of transcription factors, IRF4 is a pivotal mediator of the development and function of B cells, T cells, dendritic cells (DCs) and other immune cells. A multimorphic point mutation in the DNA-binding domain of IRF4 (p.T95R) leads to severe combined immunodeficiency in patients, characterised by a particular susceptibility to T cell-mediated infections. Yet, these patients retained relatively normal CD4+ T helper (TH) cells.
Previous work in our group demonstrated that mice with the homologous mutation in IRF4 were protected from experimental autoimmune encephalomyelitis (EAE), a TH17-driven disease model. Contrasting to Irf4-/- mice, the adoptive transfer of wild type CD4+ T cells into Irf4T95R/T95R mice failed to restore T cell functionality and EAE disease progression. These results pointed to the unique existence of an additional T cell-extrinsic defect in mice with the IRF4T95R mutation.
As DCs are key orchestrators of T cell activation and differentiation, they were a natural target for subsequent investigation. DC-T cell co-culture assays revealed no blanket defect in the ability of Irf4T95R/T95R splenic DCs to stimulate CD4+ T cell proliferation and activation. However, T cells cultured with Irf4T95R/T95R DCs showed defective differentiation into TH17 cells after restimulation, accompanied by an uncharacteristic increase in TH1 polarisation.
Conventional DC types 1, 2A, and 2B (cDC1, cDC2A, cDC2B respectively) have typically been associated with distinct TH cell responses. In T cell co-cultures with sorted DC subsets, we confirmed that the impairment in TH17 polarisation was attributable to Irf4T95R/T95R cDC2As and cDC2Bs, but not cDC1s. Conversely, all three DC subsets from Irf4T95R/T95R mice induced higher levels of TH1 differentiation. Together, these results highlight a critical role for IRF4 in programming DC subset function and in shaping downstream T cell responses.