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Early human thymocyte proliferation is regulated by an externally
controlled autocrine transforming growth factor-beta 1 mechanism
MD Mossalayi, F Mentz, F Ouaaz, AH Dalloul, C Blanc, P Debre and FW Ruscetti
Molecular Immuno-Hematology Group, Pitie-Salpetriere Hospital, Paris,
France.
Early thymocytes undergo extensive proliferation after their entry into the
thymus, but cellular interactions and cytokines regulating this intrathymic
step remain to be determined. We analyzed the effects of various T-cell
growth factors and cellular interactions on in vitro proliferation of early
CD2+CD3/TCR-CD4-CD8- (triple negative [TN]) human thymocytes. Freshly
isolated TN cells were then assayed for their growth capacity after
incubation with CD2I+III-monoclonal antibody (MoAb), recombinant human
interleukin-2 (IL-2), IL-7, and/or IL-4. These cells displayed significant
proliferative responses with IL-4, IL- 7, or CD2-MoAb+IL-2. The addition of
recombinant transforming growth factor beta (TGF beta) or autologous
irradiated CD3+CD8+CD4- cells to TN cell cultures dramatically decreased
their growth responses to IL-2 and IL-7, whereas IL-4-induced proliferation
was less sensitive to growth inhibition. We thus asked whether the CD8+
cell-derived inhibitory effect was due to TGF beta. The addition of
neutralizing anti-TGF beta MoAb completely abolished CD8+ cell-derived
inhibition of TN cell growth. Analysis of CD8+ cell-derived supernatants
indicated 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 active
inhibitory form through interaction of TN cells with CD8+ cells. Together,
these data suggest a role for TGF beta 1 as an externally controlled,
autocrine inhibitory factor for human early thymocytes, with a regulatory
role in thymic T-cell output.
Volume 85,
Issue 12,
pp. 3594-3601,
06/15/1995
Copyright © 1995 by The American Society of Hematology
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