Regulation of in vitro cytotoxic T lymphocyte generation. III. Interactions or regulatory T cell subsets in suppressor and target populations.

During allogeneic mixed leukocyte cultures (MLC), cytotoxic T lymphocytes (CTL) and at least two kinds of suppressor T lymphocyte (Ts) functions are induced. One Ts, termed nonspecific (TsN), can suppress the in vitro generation of CTL when it is transferred to any allogeneic MLC. The other Ts has specificity for MLC in which stimulator cells are homologous at the major histocompatibility complex (MHC) with stimulator cells used to induce the Ts (TsS). Previously, we have shown that addition of a 10(-4)M concentration of the histamine1 antagonist pyrilamine to the MLC strongly influences the kind of T cell function generated. That is, the generation of CTL and TsN are inhibited while the induction of TsS is not. CTL precursors are activated (CTL-PA) in such cultures, as witnessed by their differentiating in such cultures, as witnessed by their differentiating into CTL effectors upon removal of pyrilamine and transfer to a salubrious environment (e.g., any fresh MLC). This second step in the differentiation of CTL can be prevented by exposure of pyrilamine-treated MLC derived cells to greater than or equal to 500 rads gamma irradiation. Therefore, by using these combined in vitro manipulations, under the proper experimental conditions, it is possible to study TsS in the absence of both TsN and CTL. In the present studies we have used antibodies to the cell surface alloantigens Lyt 1, Lyt 2 and TL/Qa-1 to ask whether TsN and TsS also can be separated by virtue of their having different cell surface phenotypes. In addition, we have explored for the existence of interactions between subsets of T cells in the suppression of CTL generation, and whether these interactions (circuits) are akin to those previously demonstrated to be important in the regulation of B cell responses to antigen. Since CTL generation likely is important in the host defense against viruses and other pathogens, neoplasms, and transplants of foreign tissues, a firm understanding of regulatory interactions modifying this response is important. Our experimental approach has involved a technique found to be successful in the dissection of T cell regulation of B cell responses, i.e., negative selection with alloantigen-specific antibodies and complement (C'). We have found that immune Lyt 1+2+ (Ly 123) T lymphocytes are strongly involved in MLC-induced nonspecific suppression, but are not required for the expression of specific suppression. Rather, both immune Lyt 1+2- (Ly 1) and Lyt 1-2+ (Ly 2) T lymphocytes appear to be involved in optimal TsS function.(ABSTRACT TRUNCATED AT 400 WORDS)