title: Autocrine regulation of T-lymphocyte proliferation: differential induction of IL-2 and IL-2 receptor.
abstract: Three stimuli were used to compare the signals necessary for interleukin (IL-2) receptor expression and IL-2 production: triggering of the T-cell antigen receptor/CD3 complex (Ti/CD3) by CD3 antibodies, activation of protein kinase C (PKC) by phorbol esters, and elevation of intracellular calcium levels by calcium ionophore. The salient observations were that IL-2 responsiveness, which reflects IL-2 receptor expression, and T-cell proliferation which requires both IL-2 production and IL-2 receptor expression, are not co-ordinately regulated. Firstly, a low threshold of CD3 activation or a brief (1 hr) exposure of T cells to maximal CD3 stimulation is sufficient to induce IL-2 responsiveness, but higher levels of activation for a prolonged period are necessary to ensure a T-cell proliferative response. Secondly, in response to optimal T-cell stimulation there is a short (2-4 day) period of T-cell proliferation followed by a prolonged phase of IL-2 responsiveness (10-14 days). Differences in the kinetics and signalling requirements for IL-2 receptor expression and IL-2 production, regulated at the level of mRNA expression, provide a molecular basis for these observations. A major difference between induction of IL-2 production and IL-2 receptor expression is that the dual signals of calcium and PKC are necessary for IL-2 production, but a sole stimulus of PKC is sufficient for IL-2 receptor expression. Also, a low level stimulation of PKC will induce IL-2 receptor expression but higher levels of PKC stimulation are required for IL-2 production. As a consequence, triggering of a single receptor, namely the Ti/CD3 complex, results in IL-2 responsiveness, but an additional signal that activates PKC is necessary for IL-2 production. These observations suggest that a Ca2+/PKC dual signal model does not explain completely the signal transduction pathways that regulate T-cell growth. Moreover, precise regulatory mechanisms have evolved to control the homeostasis of the autocrine proliferative response of a T-cell population.
authors.affiliation: Imperial of Cancer Research Fund, London, U.K.
authors.forename: D A
authors.initials: DA
authors.lastname: Cantrell
authors.forename: M K
authors.initials: MK
authors.lastname: Collins
authors.forename: M J
authors.initials: MJ
authors.lastname: Crumpton
mesh_terms: D000911:Antibodies, Monoclonal / Q000276:immunology; D002478:Cells, Cultured; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation; D011493:Protein Kinase C / Q000276:immunology; D012333:RNA, Messenger / Q000032:analysis; D015375:Receptors, Interleukin-2 / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D007376:Interleukin-2; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D011493:Protein Kinase C