Mutual expression of the transcription factors Runx3 and ThPOK regulates intestinal CD4+ T cell immunity

CD4+ and CD8+ T cells are considered distinct functional lymphocyte subsets. Cheroutre and Mucida and their colleagues show that mature gut-associated CD4+ T cells lose ThPOK expression and reactivate CD8 cytolytic effector programs. The gut mucosa hosts large numbers of activated lymphocytes that are exposed to stimuli from the diet, microbiota and pathogens. Although CD4+ T cells are crucial for defense, intestinal homeostasis precludes exaggerated responses to luminal contents, whether they are harmful or not. We investigated mechanisms used by CD4+ T cells to avoid excessive activation in the intestine. Using genetic tools to label and interfere with T cell–development transcription factors, we found that CD4+ T cells acquired the CD8-lineage transcription factor Runx3 and lost the CD4-lineage transcription factor ThPOK and their differentiation into the TH17 subset of helper T cells and colitogenic potential, in a manner dependent on transforming growth factor-β (TGF-β) and retinoic acid. Our results demonstrate considerable plasticity in the CD4+ T cell lineage that allows chronic exposure to luminal antigens without pathological inflammation.