These mice are subsequently challenged with TT (without adjuvant), which results in not only cytokine production, including IL-2 and IFN-γ, by TT-specific memory CD4+ T cells, but also stimulates the pre-activated OT-II T cells. Notably, the use of mice not exposed to a TT prime-boost regimen (thus not containing TT-specific memory CD4+ T cells) prior to adoptive transfer of pre-activated OT-II T cells or the adoptive transfer of naïve OT-II T cells into

TT-prime-boosted mice fails to induce I-BET-762 bystander activation of pre-activated or naïve OT-II T cells, respectively, following TT challenge. Interestingly, TT booster-induced bystander activation of pre-activated OT-II T cells correlates with IL-2 and IFN-γ production in TT-specific memory CD4+ T cells. Moreover, pre-activated OT-II T cells express high levels of IL-2 receptors α and β (CD25 and CD122, respectively), as well as high levels of IL-7Rα (CD127), and proliferate strongly in the presence of IL-2 or IL-7 in vitro. selleckchem These data suggest that TT challenge leads to marked IL-2 production by TT-specific memory CD4+ T cells, thus causing IL-2-mediated bystander proliferation of pre-activated OT-II CD4+ T cells. A question that arises is to what extent these results are applicable to the in vivo situation, especially in terms of the

cytokine signals implicated and the CD4+ T cells responding to them. Previous reports showed that bystander activation of CD4+ T cells was confined to the CD44high memory subset and that the kinetics of activation in the CD44high MP CD4+ cells was similar to that of the MP CD8+ T cells 1, 2, suggesting that the same cytokine, namely IL-15, might be implicated in both processes (Fig. 1). Indeed, CD44high MP CD4+ T cells express intermediate levels of CD122 7 and might thus respond not only to IL-15, but also to IL-2. Moreover, other data suggest that IL-2 might be implicated in bystander activation of CD8+ T cells

8, 12, which is consistent with the data of Di Genova et al. on CD4+ T cells 8, 12. As for the in tuclazepam vitro pre-activated CD4+ T cells used by Di Genova et al. 8, 12, these cells are clearly different from memory CD4+ T cells, the latter of which are known to express low levels of CD25, intermediate levels of CD122, and high levels of CD127 13, 14. Moreover, memory CD4+ T cells are known to be responsive to IL-7 and IL-15 signals under steady-state conditions in vivo 14, 15, while in vitro pre-activated CD4+ T cells are, by contrast, very sensitive to IL-2 and IL-7, but not IL-15 12. This discrepancy in the IL-2- and IL-15-responses further illustrates that in vitro pre-activated CD4+ T cells crucially depend on high surface expression of CD25, as the other two IL-2 receptor subunits, CD122 and γc should have been sufficient to confer responsiveness to IL-15.