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 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.
Mossalayi
M D
MD
Molecular Immuno-Hematology Group, Pitié-Salpêtrière Hospital, Paris, France.
Mentz
F
F
Ouaaz
F
F
Dalloul
A H
AH
Blanc
C
C
Debré
P
P
Ruscetti
F W
FW
D015704:CD4 Antigens / Q000096:biosynthesis*; D016827:CD8 Antigens / Q000096:biosynthesis*; D002450:Cell Communication / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D002675:Child, Preschool; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D007378:Interleukins / Q000494:pharmacology; D016176:T-Lymphocyte Subsets; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D013950:Thymus Gland / Q000166:cytology*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000494:pharmacology
D015704:CD4 Antigens; D016827:CD8 Antigens; D007378:Interleukins; D016212:Transforming Growth Factor beta