Regulation of T cell subsets from naive to memory.

To gain insights into the development and regulation of immune responses, we have studied the phenotype, cytokine profiles, activation requirements, and susceptibility to apoptosis of naive CD4, Th1, Th2 polarized effectors, resting memory, and memory effector cells. T cell receptor (TCR) transgenic mice were utilized as a source of enriched naive cells that could be used to generate effector and memory populations. The direct comparison of these populations, which all bear the same TCR, has revealed some interesting distinctions. When restimulated with antigen, effector populations secrete high titers of cytokines in polarized patterns. Retaining their polarized profile, memory cells secrete low levels and memory effector cells secrete very large levels of cytokine. Unlike naive CD4 T cells, effector cell proliferation is not dependent on classic co-stimulation but does require a threshold level of TCR signaling that can be enhanced by accessory interactions. Memory cells have intermediate requirements for co-stimulation/accessory interactions. However, different thresholds of activation are required for production of various cytokines, with requirements for production of interleukin (IL) 2 >> interferon-gamma > IL-4. CD4 subsets also differ dramatically in their susceptibility to apoptosis. Naive Th2 effectors and resting memory cells undergo activation-induced cell death (AICD) 4-7 days after antigen stimulation. In contrast, both primary and memory Th1 effectors undergo rapid AICD mediated by Fas/FasL within 0.5-2 days after stimulation. AICD is substantially blocked by IL-2 and transforming growth factor-beta1, resulting in impressive effector expansion. The process of memory development from effector populations remains mysterious, but these studies suggest roles for cytokines in promoting survival.