CD3‐mediated apoptosis of human medullary thymocytes and activated peripheral T cells: Respective roles of interleukin‐1, interleukin‐2, interferon‐γ and accessory cells

Abstract

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)‐γ gene expression and secretion in the absence of interleukin (IL)‐2 gene expression; and the addition of anti‐IFN‐γ antibody prevented cell death. Apoptosis could also be prevented by cyclosporin A (CsA) treatment and could be re‐induced by the addition of IFN‐γ 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‐γ 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‐γ 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‐γ secretion.