CD4+ Cytotoxic T cells – Phenotype, Function and Transcriptional Networks Controlling Their Differentiation Pathways

•Subsets of MHC class II-restricted CD4+ T cells possess cytotoxic activity and these cells have been designated as CD4+ cytotoxic T lymphocytes (CD4 CTLs).•CD4 CTLs are generated during (chronic) viral infections and also during anti-tumor immune responses in humans and mice, suggesting important functions in host defense, however CD4 CTLs are potentially also involved in the pathology of autoimmune diseases.•There is no unique marker defining CD4 CTLs thus a combination of various surface markers as well as transcription factor expression patterns is used to define CD4 CTLs, and it is likely that several CD4 CTL subsets exist.•Transcriptional and epigenetic networks regulating CD4 CTL differentiation are still poorly understood, however an upregulation of RUNX3 expression and a down-regulation of ThPOK expression is key for CD4 CTL differentiation, and their generation is also controlled by HDAC1 and HDAC2, suggesting epigenetic mechanisms.