SUPPRESSOR T CELL CIRCUITS zyx Baruj Benacerraf, Mark I. Greene, Man-Sun Sy, and Martin E. Dorf zyxw Department of Pathology Harvard Medical School Boston, Massachusetts 021 15 INTRODUCTION Over the last few years, several laboratories have intensively studied specific suppression by antigen-specific T cells. This has revealed the existence of un- suspected complexity in the manner in which the immune response is negatively regulated by T cells. The salient findings are that (1 zyxw ) The specific suppression phenomena involve the interactions of several sets of T cells with defined prop- erties and characteristic surface markers.' (2) These T cells each produce specific factors that can be shown to mediate their precise regulatory function.2 (3) Their specificity is either for the antigen or for the immunoglobulin idiotypes that determine certain aspects of their interactions. zyxw (4) Certain of the suppres- sor T cells (Ts) in these circuits bear determinants coded for by the I-J sub- region of the murine H-2 complex, which also appears to restrict the interactions at certain critical steps in the pathway, in a way similar to the restrictions imposed by the I-A and I-E subregions on helper T cell (Th) interactions.' (5) Accordingly, suppressor T cell interactions in the circuit can be shown to be governed by both VII genes and major histocompatibility complex (MHC) genes at appropriate steps. Based primarily on the results obtained in our laboratories, where the regula- tion of several models by suppressor T cells has been investigated, we have recently proposed that T cell suppression in all murine systems proceeds by a common major pathway involving the sequential interactions of three T cell subsets with distinct properties, which we have termed Ts,, Ts,, and Ts,.' We have also proposed that this overall scheme may be used to integrate the data obtained in systems developed in other laboratories. We now propose to review the criteria that we have used to distinguish and identify the distinct cells in the pathway. We shall also describe the latest data from our laboratories on the analysis of T cell suppressor circuits, their cells, and their specific products. We shall then discuss the problems we have encoun- tered and are now facing in integrating the complex data in a generalizable scheme to determine to what extent one needs to postulate variants unique to certain systems. Finally, we shall try to address some of the major unresolved fundamental issues, such as the significance of the observed I-J restrictions at the molecular level and the possible role of antigen presentation by acccssory cells in the T cell suppressor pathway. TABLE 1 describes the criteria used to analyze the systems under investigation. The major distinguishing points con- sidered were: ( 1 ) the binding specificity of the relevant cell or factor and, in particular, whether its receptor is idiotypic (antigen specific) or anti-idiotypic, (2) the membrane phenotype and drug sensitivity of the factor producer and the acceptor cell, (3) the involvement of genetic restrictions (H-2 or V,) in 300 0077-8923/82/0392-0300 $1.75/0 zyxw 0 1982, NYAS