CD3-mediated apoptosis of human medullary thymocytes and activated peripheral T cells: respective roles of interleukin-1, interleukin-2, interferon-gamma and accessory cells.
Clonal deletion represents an important mechanism for the establishment of tolerance, by the elimination of autoreactive T cells. Deletion is accomplished by programmed cell death, termed apoptosis, induced by mobilization of the T cell receptor (TCR) on both thymocytes and mature T cells. The mechanism which drives T cells towards cell death or cell proliferation after TCR mobilization remains unclear. We show here that the mobilization of the CD3/TCR complex of both CD4+ and CD8+ single-positive medullary human thymocytes and human mature activated T cells, in the absence of accessory cells, leads to an activation-induced cell death process by apoptosis. In both cases, apoptosis was associated with interferon (IFN)-gamma gene expression and secretion in the absence of interleukin (IL)-2 gene expression; and the addition of anti-IFN-gamma antibody prevented cell death. Apoptosis could also be prevented by cyclosporin A (CsA) treatment and could be re-induced by the addition of IFN-gamma to CsA-treated cells. Addition of IL-2 had two different effects, it prevented apoptosis and also allowed proliferation in response to CD3 monoclonal antibody. Addition of IL-1, which induces IL-2 gene expression and secretion or addition of accessory cells, had the same preventive effect. These results suggest that the uncoupling of IFN-gamma and IL-2 gene expression following CD3/TCR mobilization initiates apoptosis of human T cells at several different stages during development and activation. We propose that co-signals provided by accessory cells allow a coupling of IL-2 gene and IFN-gamma gene expression, and that an essential role for IL-2 secretion in T cell activation involves the inhibition of a death program induced by IFN-gamma secretion.
Groux
H
H
Unité mixte INSERM U167-CNRS 624, Institut Pasteur, Lille, France.
Monte
D
D
Plouvier
B
B
Capron
A
A
Ameisen
J C
JC
D000938:Antigen-Presenting Cells / Q000276:immunology*; D017209:Apoptosis; D017252:CD3 Complex / Q000276:immunology*; D002478:Cells, Cultured; D015870:Gene Expression; D006801:Humans; D066298:In Vitro Techniques; D007223:Infant; D007371:Interferon-gamma / Q000502:physiology*; D007375:Interleukin-1 / Q000502:physiology*; D007376:Interleukin-2 / Q000502:physiology*; D008213:Lymphocyte Activation; D012333:RNA, Messenger / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000235:genetics; D016176:T-Lymphocyte Subsets / Q000166:cytology*; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology
D017252:CD3 Complex; D007375:Interleukin-1; D007376:Interleukin-2; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D007371:Interferon-gamma