Programming for recognition and programming for response. Separate developmental subroutines in the murine thymus.
Pre-T cells become programmed with the capacity to make functional responses to activating stimuli in a process that occurs prior to, and independently of, T-cell receptor gene rearrangement and T-cell receptor-dependent positive selection. In spite of this early programming, as differentiation proceeds further the cells enter a stage in which they appear to be unable to make any functional responses. This 'eclipse' phase begins when the cells undergo successful T-cell receptor beta-chain rearrangement and ends, with the return of their functional competence, only when they successfully traverse positive selection. These results suggest that pre-T cells are subject to two distinct subroutines of differentiation, which cannot operate at the same time: one which confers function and one which confers and selects recognition specificity. To provide a possible molecular basis for the relationship between these two processes, we consider specific alterations in response-associated transcription factors that may cause the changes in responsiveness observed during programming for recognition. The interplay of the two differentiation subroutines is proposed to be a consequence of the use of common transcription factors in different combinatorial contexts for functional responses, assembly of T-cell receptor complexes, and selection.