Memory effectors: a potent, IL-4-secreting helper T cell population that develops in vivo after restimulation with antigen
Bradley, L.M.; Duncan, D.D.; Yoshimoto, K.; Swain, S.L.
Journal of Immunology 150(8 Pt 1): 3119-3130
1993
ISSN/ISBN: 0022-1767 PMID: 8096850 Document Number: 408725
Resting CD4+ memory T cells from the spleens of mice primed more than 6 wk earlier with KLH in adjuvant produce IL-2 and IL-3, but only low levels of IL-4 and IFN-gamma, and undetectable IL-5 after specific restimulation in vitro. In contrast, when previously primed mice are boosted by i.v. injection of soluble KLH, a CD4+ T cell population develops in the spleen that can produce greatly increased levels of IL-4, and variably increased IL-2, IFN-gamma, and/or IL-3. The ability of these memory effector Th cells to be restimulated to secrete cytokines is maximal by 3 days after in vivo boosting with Ag, and declines rapidly thereafter. Memory effector Th are induced in the spleens of KLH-primed mice that have been depleted of precursor T cells by thymectomy more than 25 wk previously, suggesting that they are derived from a memory T cell population. Cell separation on the basis of CD45RB or MEL-14, surface markers that are down-regulated on memory CD4+ cells, indicates that memory effector Th are in the CD45RB-lo and MEL-14- subsets of CD4+ T cells. The frequency of KLH-specific splenic CD4+ T cells with the capacity to secrete cytokines in limiting dilution cultures is very low in unprimed mice (1/3 times 10-4 to 1/9 times 10-4), but increases as much as 50-fold after priming. IL-2, but not IL-4, can be detected in the supernatants of stimulated unprimed CD4+ T cells. Both IL-2- and IL-4-producing cells are readily detected after priming, and frequencies of IL-2-secreting cells (1/250 to 1/4000) are up to ninefold greater than those for IL-4 secreting cells. Boosting elicits variable (two to eightfold) increases in the frequencies of both IL-2- and IL-4-producing CD4+ T cells. However, high IL-4 titers associated with memory effector Th function can be obtained when significant frequency changes are not detected after boosting. The data suggest that reactivation of resting memory Th in vivo induces their differentiation into effector Th with the capacity to secrete much higher levels of IL-4. Although the capacity to produce high levels of IL-4 is associated with both primary and memory CD4+ effector populations, memory effector Th are the higher producers. Memory effector Th are also by far the most effective helper cells, and the only population that can help hapten-primed B cells to secrete high titers of IgG1 as well as moderate titers of IgG3, IgG2a, and IgG2b, in addition to IgM. We propose that memory Th differentiate into memory effectors rapidly after stimulation with Ag and that memory effectors are likely to be a major population regulating the development of memory responses.