Views on helper/cytotoxic lineage choice from a bottom‐up approach

Summary There has been speculation as to how bi‐potent CD 4 +   CD 8 + double‐positive precursor thymocytes choose their distinct developmental fate, becoming either CD 4 + helper or CD 8 + cytotoxic T cells. Based on the clear correlation of αβT cell receptor (TCR) specificity to major histocompatibility complex (MHC) classes with this lineage choice, various studies have attempted to resolve this question by examining the cellular signaling events initiated by TCR engagements, a strategy referred to as a ‘top‐down’ approach. On the other hand, based on the other correlation of CD 4/ CD 8 co‐receptor expression with its selected fate, other studies have addressed this question by gradually unraveling the sequential mechanisms that control the phenotypic outcome of this fate decision, a method known as the ‘bottom‐up’ approach. Bridging these two approaches will contribute to a more comprehensive understanding of how TCR signals are coupled with developmental programs in the nucleus. Advances made during the last two decades seemed to make these two approaches more closely linked. For instance, identification of two transcription factors, Th POK and Runx3, which play central roles in the development of helper and cytotoxic lineages, respectively, provided significant insights into the transcriptional network that controls a CD 4/ CD 8 lineage choice. This review summarizes achievements made using the ‘bottom‐up’ approach, followed by a perspective on future pathways toward coupling TCR signaling with nuclear programs.