This model claims that a brief period of antigen stimulation in presence of CD4+ T cells is necessary to cause naïve CD8+ T cells to differentiate into effector cells that subsequently develop into long-lived protective memory CD8+ T cells. The second model suggests that the maintenance of CD8+ memory T cells requires continuous exposure to bystander CD4+ T cells far beyond the priming phase [[4]]. Instead of programming, CD4+ T cells seem to be required for the subsequent survival and maintenance of functional memory CD8+ T cells. The involvement of T-cell help in this system seems to be antigen nonspecific, however whether CD4+ T cells themselves are responsible for

the production of factors necessary for the maintenance of memory CD8+ T cells, or other cells get instructed by CD4+ T cells to provide certain signals, needs to be further investigated [[64]]. A recent finding also SCH727965 in vivo points to a role for

DAPT solubility dmso CD4+ T-cell help during the challenge phase [[57]]. Thus, it is likely that the nature of the challenge infection/immunization might be a crucial parameter in determining the T-cell help dependence of memory CD8+ T cells, a notion which we think should be carefully taken into consideration when comparing results from different experimental setups. An important feature of T helper cells is the production of IL-2, since it was shown in various experimental settings that CD4+ T-cell derived IL-2 is a crucial mediator of T-cell help [[26, 65]]. Lately, there is also growing interest in the role of IL-2 in the differentiation process of CD8+ T cells in T-cell help-independent experimental settings. Although IL-2R deficient CD8+ T cells show only a modest impairment in their ability to make robust primary response upon infection with LCMV, IL-2 signaling during the priming seems to be required for the ability

of the ensuing CD8+ memory cells to mount optimal secondary responses [[66, 67]]. More recent data further clarified these findings, Histamine H2 receptor showing that an early transient heterogeneity of CD25 expression on LCMV-specific CD8+ T cells directs them into different developmental programs, with increased CD25 expression, and hence increased sensitivity towards IL-2 signals, favoring effector cell differentiation at the expense of memory cell differentiation [[68, 69]]. Thus, although it remains unclear whether CD4+ T cells are the critical source of IL-2 in this process, these studies clearly indicate that the magnitude and duration of IL-2 signals can have a striking influence early on in CD8+ T-cell differentiation. In contrast to the data obtained with LCMV infection, the recall capacity of L. monocytogenes-specific memory cells was found to be independent of IL-2 signaling [[70]]. It should be mentioned that besides T-helper cells, DCs, and CD8+ T cells are also capable in producing IL-2.