EARLY HUMAN THYMOCYTE PROLIFERATION IS REGULATED BY AN EXTERNALLY CONTROLLED AUTOCRINE TRANSFORMING GROWTH-FACTOR-BETA-1 MECHANISM

Early thymocytes undergo extensive proliferation after their entry int o the thymus, but cellular interactions and cytokines regulating this intrathymic step remain to be determined. We analyzed the effects of v arious T-cell growth factors and cellular interactions on in vitro pro liferation of early CD2(+)CD3/TCR(-)CD4(-)CD8(-) (triple negative [TN] ) human thymocytes. Freshly isolated TN cells were then assayed for th eir growth capacity after incubation with CD2(I+III)-monoclonal antibo dy (MoAb), recombinant human interleukin-2 (IL-2), IL-7, and/or IL-4. These cells displayed significant proliferative responses with IL-4, I L-7, or CD2-MoAb+IL-2. The addition of recombinant transforming growth factor beta (TGF beta) or autologous irradiated CD3(+)CD8(+)CD4(-) ce lls to TN cell cultures dramatically decreased their growth responses to IL-2 and IL-7, whereas IL-4-induced proliferation was less sensitiv e to growth inhibition. We thus asked whether the CD8(+) cell-derived inhibitory effect was due to TGF beta. The addition of neutralizing an ti-TGF beta MoAb completely abolished CD8(+) cell-derived inhibition o f TN cell growth. Analysis of CD8(+) cell-derived supernatants indicat ed that these cells had low TGF beta 1 production capacity, whereas TN cells secrete significantly high levels of TGF beta 1. Cell fixation studies showed that TN cells were the source of the TGF beta. TGF beta 1 released from TN cells was in the latent form that became the activ e inhibitory form through interaction of TN cells with CD8(+) cells. T ogether, these data suggest a role for TGF beta 1 as an externally con trolled, autocrine inhibitory factor for human early thymocytes, with a regulatory role in thymic T-cell output. (C) 1995 by The American So ciety of Hematology.