Control by positive and negative regulatory cells of the generation of antigen-specific suppressor T cells that inhibit cytotoxic T cell responses to alloantigens.

Abstract

The induction of a cytotoxic T cell response requires interaction with T helper (TH) cells and can be suppressed by T suppressor (TS) cells. However the control mechanisms that regulate the regulatory cells themselves have not been clearly elucidated. We have designed a three-step sequential culture system to analyze the regulatory controls operating on antigen-specific Ts cells active in the inhibition of CTL responses to alloantigen. The generation of T suppressor cells requires a positive collaborative interaction with a Ts-directed helper cell and is negatively regulated by interaction with a TS-directed inhibitory T cell. In the system described, both Lyt 1+2- and Lyt 1-2+ radioresistant effector TS are observed. The suppressive effect of these is subject to negative control by a T cell inhibitor. The Lyt 1-2+ Ts have been directly shown to be strongly inhibited by Lyt 1+2+ TS-directed inhibitors. Analysis of the regulatory effects mediated by populations of cells treated with anti-Thy 1.2 or anti-Lyt antibodies indicates a very complex network of TH and T inhibitors acting to control antigen-specific TS generation. An antigen-specific immune network is proposed to explain the control of CTL responses and the regulators of CTL responses and is discussed in light of our experimental observations on the positive and negative control of the generation of TS.