Three-cell-type clusters of T cells with antigen-presenting cells best explain the epitope linkage and noncognate requirements of the in vivo cytolytic response.

Using an established i.p. adoptive transfer system in which primed precursors of cytolytic (Tc) cells are combined with primed helper (Th) cells and alloantigen, the three-cell-type hypothesis of T-T cooperation has been tested. This hypothesis assumes that cooperation takes place through the formation of clusters, consisting of one or more Tc precursors plus one or more Th cells binding to antigen on the surface of antigen-presenting cells (APC). By using antigens in which the H-2Db epitopes recognized by the Tc precursors are presented either on the same cell as the BALB minor histocompatibility epitopes recognized by the Th cells, or a different one, the value of epitope-linkage has been explored. Epitope-linkage is found to enhance the response at low concentrations of antigen but not at high ones, in accordance with the prediction that at low concentrations individual APC will usually take up either one antigen or the other but not both from an unlinked mixture, while at high concentrations most APC will take up both whether they are linked or not. In a further test of this hypothesis, no requirement for a cognate T-T interaction could be detected. With the three-cell-type interaction thus better established, its implications in terms of efficiency compared with linked-cognate interactions and its evolution are discussed.