Pathways and mechanisms of CD4⁺CD8αα⁺ intraepithelial T cell development

The mammalian small intestine epithelium harbors a peculiar population of CD4⁺CD8αα⁺ T cells that are derived from mature CD4⁺ T cells through reprogramming of lineage-specific transcription factors. CD4⁺CD8αα⁺ T cells occupy a unique niche in T cell biology because they exhibit mixed phenotypes and functional characteristics of both CD4⁺ helper and CD8⁺ cytotoxic T cells. The molecular pathways driving their generation are not fully mapped. However, recent studies demonstrate the unique role of the commensal gut microbiota as well as distinct cytokine and chemokine requirements in the differentiation and survival of these cells. We review the established and newly identified factors involved in the generation of CD4⁺CD8αα⁺ intraepithelial lymphocytes (IELs) and place them in the context of the molecular machinery that drives their phenotypic and functional differentiation.