Modelling T-cell-mediated suppression dependent on interactions in multicellular conjugates

Tolerance to peripheral body antigens involves multiple mechanisms, namely T-cell-mediated suppression of potentially autoimmune cells. Recent in vivo and in vitro evidence indicates that regulatory T cells suppress the respo nse of effector T cells by a mechanism that requires the simultaneous conju gation of regulatory and effector T cells with the same antigen-presenting cell(APC). Despite this strong requirement, it is not yet clear what happen s while both cells are conjugated. Several hypotheses are discussed in the literature. Suppression may result from simple competition of regulatory an d effector cells for activation resources on the APC; regulatory T cells ma y deliver an inhibitory signal to effector T cells in the same conjugate; o r effector T cells may acquire the regulatory phenotype during their intera ction with regulatory T cells. The present article tries to further our und erstanding of T-cell-mediated suppression, and to narrow-down the number of candidate mechanisms. We propose the first general formalism describing th e formation of multicellular conjugates of T cells and APCs. Using this for malism we derive three particular models, representing alternative mechanis ms of T-cell-mediated suppression. For each model, we make phase plane and bifurcation analysis, and identify their pros and cons in terms of the rela tionship with the large body of experimental observations on T-cell-mediate d suppression. We argue that accounting for the quantitative details of ado ptive transfers of tolerance requires models with bistable regimes in which either regulatory cells or effecters cells dominate the steady state. From this analysis, we conclude that the most plausible mechanism of T-cell-med iated suppression requires that regulatory T cells actively inhibit the gro wth of effector T cells, and that the maintenance of the population of regu latory T cells is dependent on the effector T cells. The regulatory T cell population may depend on a growth factor produced by effector T cells and/o r on a continuous differentiation of effector cells to the regulatory pheno type. (C) 2000 Academic Press.