title: 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.
authors.affiliation: Division of Biology, California Institute of Technology, Pasadena 91125.
authors.forename: E V
authors.initials: EV
authors.lastname: Rothenberg
authors.forename: R A
authors.initials: RA
authors.lastname: Diamond
authors.forename: K A
authors.initials: KA
authors.lastname: Pepper
authors.forename: J A
authors.initials: JA
authors.lastname: Yang
mesh_terms: D000818:Animals; D000943:Antigens, Differentiation / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens; D002454:Cell Differentiation; D015870:Gene Expression; D007375:Interleukin-1 / Q000494:pharmacology; D007376:Interleukin-2 / Q000235:genetics*; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D011828:Radiation Chimera; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology*; D013950:Thymus Gland / Q000166:cytology; D013997:Time Factors
chemical_list: D000943:Antigens, Differentiation; D000945:Antigens, Differentiation, T-Lymphocyte; D015704:CD4 Antigens; D016827:CD8 Antigens; D007375:Interleukin-1; D007376:Interleukin-2; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell