Evidence that TGF-beta can inhibit human T-lymphocyte proliferation through paracrine and autocrine mechanisms.
Transforming growth factor-beta (TGF-beta) has been documented as having an inhibitory effect on the proliferation and growth of human T-lymphocytes. We examined the relative contribution of both exogenous and endogenous TGF-beta to this inhibitory action. Purified human peripheral blood T-cells were cultured with Con A (0.2 microgram/ml), washed with methyl mannopyranoside, and then cultured in rIL-2 (5 U/ml) with or without TGF-beta (80 pM). Proliferation, as measured by uptake of tritiated thymidine at 72 hr, was inhibited by added active TGF-beta. Addition of neutralizing anti-TGF-beta antibodies at the initiation of culture abrogated the antiproliferative effects of TGF-beta. A mink lung cell bioassay was used to measure endogenous TGF-beta production by the T-cells following transient acidification of the supernatants to activate latent TGF-beta. T-lymphocytes cultured with rIL-2 alone produced low levels of TGF-beta, first detectable at 72 hr. The addition of (active) TGF-beta to these cultures resulted in earlier and higher levels of endogenously produced latent TGF-beta protein. This was reflected at the mRNA level as well. The exogenously added active TGF-beta appeared to be depleted during the culture period, presumably by the activated T-cells, which exhibited elevated levels of types I, II, and III TGF-beta receptors. The increase in TGF-beta protein levels was due to endogenous TGF-beta synthesis and secretion as supported by a capture assay using 35S-labeled culture supernatants. These findings indicate that both paracrine and autocrine mechanisms are involved in the inhibitory effects of TGF-beta on the proliferation of normal human T-lymphocytes and suggest that other TGF-beta-producing cells can augment production of TGF-beta by activated T-lymphocytes.
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Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104-6082.
Ford
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Douglas
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Cherian
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Nowell
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D004334:Drug Administration Schedule; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage; D008213:Lymphocyte Activation / Q000187:drug effects*; D012333:RNA, Messenger / Q000235:genetics; D011956:Receptors, Cell Surface / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta; D013601:T-Lymphocytes / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000494:pharmacology*
D007376:Interleukin-2; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta