IL-2 gene inducibility in T cells before T cell receptor expression. Changes in signaling pathways and gene expression requirements during intrathymic maturation

Abstract

The ability to express the growth hormone IL-2 upon stimulation gives T lymphocytes one of their major effector functions in the immune system. IL-2 is apparently synthesized only by T cells, and only by a subset of T cells which constitutes a "helper" class. It remains unknown how and when the IL-2-producing lineage becomes distinct from other functional effector lineages. We have therefore examined immature T cell precursors to determine when IL-2 inducibility is acquired in relation to other maturation events, such as expression of an Ag-binding TCR, which is suspected to play an influential role in the determination of subclass commitment. In mature T cells, IL-2 is inducible via agonists of the phosphoinositide pathway, a network of signaling mediators shared by a wide variety of metazoan cell types. The universality of this activation pathway makes it seem less likely, a priori, to be a target of developmental change than the intrinsic susceptibility to induction of the IL-2 locus. However, our results presented here refute this expectation. In this report, we show that both TCR+ cells and pre-T cells too immature to express TCR can be induced to express IL-2 at high levels. The induction requirements for IL-2 expression, however, are different in TCR- and TCR+ cells. Even by using Ca2+ ionophore and phorbol ester to bypass the requirement for the TCR in cell activation, the TCR- cells also require the presence of the polypeptide hormone IL-1. By contrast, TCR+ mature cells not only can express IL-2 without IL-1, but also show no response to IL-1 when Ca2+ ionophore and phorbol ester are present. IL-1-dependent IL-2 producers appear in the thymus of repopulating radiation chimeras before "mature" (TCR+) T cells, whereas IL-1-independent IL-2 production is found only afterward. Thus, IL-2 inducibility per se apparently precedes TCR expression and all TCR-associated fate determination events. However, developmental alteration of signal transduction pathways may play a vital regulatory role in the later allocation of particular functional responses to appropriate lineages of T cells.