‘All things considered’: transcriptional regulation of T helper type 2 cell differentiation from precursor to effector activation

Summary T helper type 2 ( T h2) cells are critical to host defence against helminth infection and the pathogenesis of allergic diseases. The differentiation of T h2 cells from naive CD 4 T cells is controlled by intricate transcriptional mechanisms. At the precursor stage of naive CD 4 T cells, transcriptional mechanisms maintain the potential and in the meantime prevent spontaneous differentiation to T h2 fate. In addition, intrachromosomal interactions important for co‐ordinated expression of T h2 cytokines pre‐exist in naive CD 4 T cells. Upon T ‐cell receptor ( TCR ) engagement, naive CD 4 T cells are induced by polarizing signals of the interleukin‐4/ S tat6 and J agged/ N otch pathways to up‐regulate the expression of GATA ‐3. Once up‐regulated, GATA ‐3 drives T h2 and suppresses T h1 differentiation in a cell autonomous fashion. In this stage of differentiation, the T h2 cytokine locus, as well as the interferon‐γ locus, undergoes chromatin remodelling and epigenetic modifications that contribute to the somatic memory of T h2 cytokine gene expression pattern. Once differentiated, T h2 effector cells promptly produce T h2 cytokines upon TCR stimulation, which is regulated by concerted actions of GATA ‐3, TCR signalling, enhancers and the T h2 locus control region. This review provides a detailed account of the transcriptional regulatory events at these different stages of T h2 differentiation.