Effector T cell differentiation: are master regulators of effector T cells still the masters?

•Teff cell differentiation is orchestrated by complex transcriptional network.•Master transcription factors are preceded by pioneering factors.•Operate within metabolic and epigenetic landscape.•Cooperate with other regulators to define Teff lineage specificity.

Effector CD4 T cell lineages have been implicated as potent inducers of autoimmune diseases. Tbet, Gata3 and Rorgt are master transcriptional regulators of Th1, Th2 and Th17 lineages respectively and promote the distinct expression of signature cytokines. Significant progress has been made in understanding the transcriptional network that drives CD4 T cell differentiation, revealing novel points of regulation mediated by transcription factors, cell surface receptors, cytokines and chemokines. Epigenetic modifications and metabolic mediators define the transcriptional landscape in which master transcription factors operate and collaborate with a network of transcriptional modifiers to guide lineage specification, plasticity and function.