A T cell clone's avidity is a function of its activation state

At present it is unclear how Ag dose-dependent T cell functions, such as cy tokine production, reflect TCR affinity and how the signal strength afforde d by the Ag dose affects the kinetics of cytokine production by the individ ual T cell. We used a computer-assisted ELISPOT approach to address these i ssues. IFN-gamma release by a clonal population of CD4 T cells was monitore d on a clonal population of APC while titrating the nominal peptide. The fr equency of cytokine-producing cells, the net per-cell output of cytokine, a nd the onset of cytokine production were each found to be functions of the signal strength. Sigmoidal dose-response curves were seen at the clonal pop ulation level, but the activation thresholds for the individual T cells fol lowed a Gaussian distribution. Moreover, the overall dose-response curve of the T cell clone revealed cyclic changes, becoming increasingly shifted to ward lower Ag concentrations with the duration of time that elapsed since t he last restimulation with Ag. Therefore, responsiveness to Ag ("functional avidity") is not a constant parameter of a T cell clone but a function of the T cell's history of last Ag encounter. The implications of such shiftin g activation thresholds are discussed for autoimmune disease.