FIGURE 2

Proposed network for regulatory interactions in CD4/CD8-lineage choice. The figure summarizes the interactions described in the text. Here, (a) indicates the position of the activating inputs required for Thpok (Zbtb7b) induction and the mutual positive feedback of Thpok on GATA-3; (b) shows the Runx repression of Thpok and its antagonism by Thpok itself, in parallel with the similar action on the Cd4 gene silencer; (c) shows the repressive input of Thpok on the distal promoter of Runx3, which is one key element of the prohibition of CD8⁺-cell differentiation by Thpok. It is not clear whether the Thpok effects on GATA-3 or on the Runx3 promoter are direct, and the exact mechanism for Runx3 repression of Thpok is also under intense study. Additional effects of Thpok on CD8⁺-cell-associated genes are shown based on Jenkinson et al. ²⁷ and Wang et al. ²⁸ The exact regulatory control that positively establishes CD4⁺-cell gene expression, especially in the absence of Thpok, is not established. Note, however, that effects on the expression of CD4 and CD8 themselves can feed back on the strength and duration of TCR signaling experienced during positive selection (left of figure), depending on the major histocompatibility complex restriction of the TCR expressed.⁴