NORMAL HUMAN CD4(-CELLS DISPLAY BROAD HETEROGENEITY IN THEIR ACTIVATION THRESHOLD FOR CYTOKINE SYNTHESIS() MEMORY T)

CD4(+) memory T cells coordinate immune responses against viruses and other pathogens via the Ag-induced secretion of potent effector cytoki nes, The efficacy of these responses depends on both the overall numbe r of pathogen-specific memory T cells and the particular array of cyto kines that these cells are programmed to secrete. Here, we provide evi dence that heterogeneity in Ag triggering thresholds constitutes an ad ditional critical determinant of memory T cell function. Using a novel assay that allows single-cell detection of Ag-specific T cell cytokin e production, we demonstrate that CMV-specific CD4(+) memory cells fro m human peripheral blood display pronounced differences in their costi mulatory requirements for Ag-induced triggering of IFN-gamma and IL-2 secretion, ranging from cells that trigger with little costimulation ( e.g., resting APC alone) to cells requiring potent costimulation throu gh multiple pathways (resting APC plus multiple costimulatory mAbs, or activated APC), These differences in costimulatory requirements are i ndependent of clonal differences in TCR signaling intensity, consisten t with an intrinsic activation-threshold heterogeneity that is ''downs tream'' from the TCR, Thus, ''effective'' frequencies of Ag-specific C D4(+) memory T cells appear to depend on the activation status of avai lable APC, a dependence that would allow the immune system to rapidly adjust the number of functional Ag-specific memory T cells: in a parti cular effector site according to local conditions.