The decision of naïve T cells to differentiate into a specific Th cell subset after antigen encounter is a critical pivot point of the immune response and, when out of balance, can lead to autoimmunity, allergy or immunodeficiency. Th subset differentiation is determined by expression of transcription factors including IRF4.
Deficiency in IRF4 leads to dysregulations in all Th subsets most strikingly a complete inability to differentiate into the encephalitogenic Th17 cells. In consequence, Irf4-/- mice are completely protected from the Th17 cell dependent experimental autoimmune encephalomyelitis model (EAE) of neuroinflammation and this protection can be overcome by the adaptive transfer of IRF4 competent T cells.
We here investigate a variety of point mutations in the DNA binding domain of IRF4.
Each mutation displays a distinct pattern of T cell differentiation, with elevated or reduced subsets depending on the mutation. Two of these mutations are protected in the EAE model despite the in vitro capability to produce Th17 cells and this protection cannot be broken by T cell transfer. Our data indicats a multi-morphic effect of these point mutations in a key transcription factor, T cell intrinsic and extrinsic, altering it’s role in neuroinflammation.