Figure 6. Environmental cues and nuclear factors that influence the CD4/CD8 decision.

Environmental cues that influence CD4/CD8 lineage choice must ultimately be translated by developing thymocytes into molecular events mediated by nuclear factors that differentially affect co-receptor gene expression. Here, we consider the interactions among four different transcription factors: Th-POK (T-helper-inducing POZ/Kruppel-like factor), RUNX3 (runt-related transcription factor 3), TOX (thymus high-mobility group box protein) and GATA3 (GATA-binding protein 3). Three of these factors are important for CD4⁺ T-cell differentiation (Th-POK, TOX and GATA3), and only one (RUNX3) is known to be important for CD8⁺ T-cell differentiation. During positive selection, T-cell receptor (TCR) signals upregulate TOX, GATA3 and Th-POK. TOX upregulation is necessary for TCR-signalled DP thymocytes to phenotypically become CD4⁺CD8^low intermediate thymocytes⁷⁸. GATA3 upregulation is important for the differentiation of CD4⁺CD8^low thymocytes into CD4⁺ T cells⁸², ¹⁰³. And Th-POK expression in TCR-signalled thymocytes, which is significantly upregulated in CD4⁺CD8^low intermediate thymocytes by persistent TCR signalling⁴⁷, is required for CD4-lineage commitment⁸¹, ⁸⁵, ⁹³ and for preventing Cd4 gene silencing by RUNX proteins¹¹⁷. It is not yet known what environmental signal upregulates RUNX3 expression, but it is hypothesized that its expression may be upregulated by interleukin-7 receptor (IL-7R) signalling. In any event, RUNX3 performs three important functions that promote the differentiation of intermediate thymocytes into CD8⁺ T cells: first, RUNX3 binds to the Cd4 silencer element and silences Cd4 gene expression⁹⁵; second, RUNX3 binds to the E8_I Cd8 enhancer element and re-initiates Cd8 gene expression⁸³, and third RUNX3 silences Th-POK gene expression⁸⁴.