Tolerance induction of human CD4+ T cells: markedly enhanced sensitivity of memory versus naive T cells to peripheral anergy.

We have previously demonstrated that freshly isolated highly purified normal human peripheral blood CD4+ T cells pulsed with an IgM anti-CD3 mAb, 38.1, or the calcium ionophore, ionomycin, retained the phenotype of normal resting T cells but exhibited markedly reduced proliferative responses upon subsequent stimulation. Using this model of anergy, the sensitivity of naive (CD45RA+) and memory (CD45RO+) T cells was examined. CD4+ T cells were separated into memory or naive subsets based on their relative expression of CD45 isoforms. The memory T cells were found to be much more susceptible than naive T cells to anergy induction. After tolerance induction, memory T cells were inhibited in the ability to respond to the recall antigen, tetanus toxoid, and PHA. Anergy appeared to result from an inability to produce sufficient IL2 and proliferative responses could be restored by large numbers of accessory cells. T cell clones could also be anergized in a similar manner, but their capacity to produce IL2 could not be restored by accessory cells. In contrast to memory cells and T cell clones, the responses of naive T cells were only minimally inhibited by tolerogen. These results suggest that tolerance induced by occupancy of the TCR/CD3 complex in the absence of appropriate costimulation may be an effective means to limit the responses of memory T cells, but that such interactions are unable to limit the subsequent responses of naive T cells.