THYMIC STROMA-DERIVED T-CELL INHIBITORY FACTOR (TSTIF) .1. TSTIF INDUCES INHIBITION OF ANTIGEN-STIMULATED T-CELL PROLIFERATION

The present study investigates the capacity of the MRL104.8a thymic st romal cell clone to modulate T-cell growth. The culture supernatant (S N) from the MRL104.8a stromal cell monolayer was added to cultures of Th-clones with or without T-cell receptor (TCR) stimulation as provide d by antigen (Ag) plus splenic antigen-presenting cells (APC). The res ults demonstrated that the MRL 104.8a SN containing IL-7 activity indu ced dose-dependent proliferation of Th cells when they were not stimul ated with Ag/APC. In contrast, addition of the same SN to cultures of Th cells during stimulation with Ag/APC resulted in potent dose-depend ent inhibition of their proliferation. IL-7 contained in the SN was ne ither responsible for, nor involved in the inhibition event, because t he inhibition was not observed with rIL-7 and was not neutralized by a nti-IL-7 antibody. The growth inhibition of the Th clone in the presen ce of Ag plus APC was also induced by IL-10 or TGF-beta. However, the MRL104.8a SN-induced growth inhibition was mediated by a factor distin ct from these cytokines, because (1) IL-10 cDNA was not amplified in p olymerase chain reaction (PCR) products derived from MRL104.8a cells; (2) TGF-beta cDNA was detected in the PCR products, but only marginal levels of TGF-beta activity in an active form were found in the MRL104 .8a SN and the SN-induced inhibition was not prevented by anti-TGF-bet a antibody; and (3) addition of rIL-7 to antigen-stimulated cultures c ontaining rTGF-beta or rIL-10 induced IL-7 mediated Th proliferation, whereas the MRL104.8a SN-induced inhibition was still observed in the presence of excess rIL-7. Moreover, this factor, designated thymic str oma-derived T-cell inhibitory factor, was found to have a m.w. of 20-2 5 x 10(3) and to exhibit heparin-binding property. Thus, these results indicate that the MRL104.8a thymic stromal cell clone produces a pote ntially novel factor that induces inhibition of antigen-stimulated T-c ell proliferation.