Signal requirements in the step-wise functional maturation of cytotoxic T lymphocytes

Abstract

The generation of effector cytotoxic T lymphocytes from resting precursors proceeds through a series of steps in a pathway that, in aggregate, involves both proliferation and development of cytotoxicity^1–7. To understand the relationship of the various signals (mitogens and/or lymphokines) that bring about progress along this pathway, it is desirable to define a series of 'minimal signals', each of which stimulates the cell to proceed to a further stage in this process of differentiation. Stimulation of lymphocytes with two different monoclonal antibodies directed against the CD2 surface molecule induces a proliferative response⁸; we report here that both CD4⁺ and CD8⁺ cells proliferate in response to such a stimulus but do not develop cytotoxicity. Addition of recombinant γ-interferon (rIFN-γ) or recombinant IL-2 (rIL-2) to the activated cells leads to acquisition of cytotoxic status by the CD8⁺ cells but not the CD4⁺ cells. The availability, in addition to precursors and effectors, of an apparently intermediate stage in the form of proliferating CD8⁺ cells that are non-cytotoxic should facilitate both cellular and molecular studies of this maturation pathway; the differences between CD4⁺ and CD8⁺ cells in development of cytotoxicity under these experimental conditions is a valuable model for understanding differentiation of T lymphocytes.