Magnitude of response of histocompatibility-restricted T-cell clones is a function of the product of the concentrations of antigen and Ia molecules.

The activation of specific T-cell clones by antigens is dependent upon the corecognition of restriction elements expressed on antigen-presenting cells (APC). For clones that respond by proliferation and lymphokine production, the restriction element is usually an Ia (I-region-associated) molecule. We show here that the magnitude of the proliferative response of such clones is a function of the product of antigen concentration and the number of Ia molecules expressed on APC. This conclusion was reached through the study of antigen concentration-response curves of T-cell clones specific for pigeon cytochrome c. These curves are characterized by a peak in thymidine incorporation, followed by a decrease in the magnitude of the response as antigen concentrations are increased. The decline in response at high concentrations was not the consequence of the emergence of suppressor cells in the APC population, as it was observed when cells of a cloned B-cell hybridoma line were used to present pigeon cytochrome c to these T-cell clones. The critical role of both antigen concentration and the number of Ia molecules on the APC in determining the magnitude of proliferation was demonstrated in several ways. (i) An inverse relationship was observed between the antigen concentration required for maximum proliferation and the number of APC present in culture. At high antigen concentrations, which caused responses less than maximum, reducing the number of APC actually increased the magnitude of the antigen-induced proliferation. (ii) Decreasing the number of relevant Ia molecules per APC (i.e., as in F1 hybrids) resulted in the requirement for an increased antigen concentration for maximal response and in enhanced proliferation at high antigen concentrations. (iii) In the presence of anti-Ia antibody, higher concentrations of antigen were required for maximal response; at high antigen concentrations, proliferation was enhanced in the presence of a monoclonal anti-Ia antibody directed against the Ia restriction element.