MPA inhibits guanine nucleotide synthesis and depletes GTP. This impacts the function of TIF-IA and in particular the capacity of TIF-IA to interact with Ebp1, an interaction that regulates rRNA synthesis via the interaction of TIF-IA with Pol I and transcription of PCNA, thus impacting T-cell proliferation and function. In addition, sotrastaurin inhibits PKCδ, which phosphorylates Ebp1 at position S360, a step required for PCNA expression. MPA and sotrastaurin synergize and inhibit T-cell activation and proliferation very potently by inhibiting the functional interaction between TIF-IA and Ebp1.