The enigma of CD4 lineage specification

CD4+ T cells are essential for defenses against pathogens and affect the functions of most cells involved in the immune response. Although CD4+ T cells generally recognize peptide antigens bound to MHC-II molecules, important subsets are restricted by other MHC or MHC-like molecules, including CD1d-restricted “invariant” iNK T cells. This review discusses recently identified nodes in the transcriptional circuits that are involved in controlling CD4+ T-cell differentiation, notably the commitment factor Thpok and its interplay with Runx transcriptional regulators, and focuses on how transcription factors acting upstream of Thpok, including Gata3, Tox and E-box proteins, promote the emergence of CD4-lineage-specific gene expression patterns.