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*
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106; and
Section of Endocrinology, University Hospital of Ulm, Ulm, Germany
At present it is unclear how Ag dose-dependent T cell functions,
such as cytokine production, reflect TCR affinity and how the signal
strength afforded by the Ag dose affects the kinetics of cytokine
production by the individual T cell. We used a computer-assisted
ELISPOT approach to address these issues. IFN-
release by a clonal
population of CD4 T cells was monitored on a clonal population of APC
while titrating the nominal peptide. The frequency of
cytokine-producing cells, the net per-cell output of cytokine, and the
onset of cytokine production were each found to be functions of the
signal strength. Sigmoidal dose-response curves were seen at the clonal
population level, but the activation thresholds for the individual T
cells followed a Gaussian distribution. Moreover, the overall
dose-response curve of the T cell clone revealed cyclic changes,
becoming increasingly shifted toward lower Ag concentrations with the
duration of time that elapsed since the 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 shifting
activation thresholds are discussed for autoimmune
disease.
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