322 PART I Immune Effector Mechanisms Class II mhc CD4 THl cell Co-stimulatory signal IL-2 HI cell Class I mhc IL-2R. Activation arget cell Ta CTL-P g-activated CTL-P Proliferation Effector cytotoxic function FIGURE 14-1 Generation of effector CTLS. Upon interaction with additional IL-2 secreted by TH1 cells resulting from antigen activation antigen-class I MHC complexes on appropriate target cells, CTL-Ps be- and proliferation of CD4"' T cells. In the subsequent effector phase, CTLS gin to express IL-2 receptors (IL-2R) and lesser amounts of IL-2 Prolif- destroy specific target cells. eration and differentiation of antigen-activated CTL-Ps generally require is particularly true of memory CTL-Ps, which have lower the immune response is rapidly terminated, lessening the activation requirements than naive cells do( figure 14-2a). likelihood of nonspecific tissue damage from the inflamma In general, though, most activated CTL-Ps require addi- tory response tional IL-2 produced by proliferating THl cells to proliferate The role of THl cells in the generation of CTls from naive and differentiate into effector CTLs. The fact that the IL-2 CTL-Ps is not completely understood, and it is unlikely that a receptor is not expressed until after a CTL-P has been acti- THl cell and CTl-P interact directly. However, IL-2 and vated by antigen plus a class I MHc molecule favors the stimulation are important in the transformation of naive clonal expansion and acquisition of cytotoxicity by only the CTL-Ps into effector cells, and THl cells can be mediators antigen-specific CTL-Ps in the provision of these essential requirements. As shown The proliferation and differentiation of both antigen- in Figure 14-2b, the interaction of helper cells with antigen activated THl cells and CTL-Ps depend on IL-2. In IL-2 presenting cells can result in production of IL-2 by the TH1 knockout mice, the absence of IL-2 has been shown to abol- cell. The paracrine action of this cytokine on nearby naive ish CTL-mediated cytotoxicity. After clearance of antigen, CTL-Ps whose TCRs are engaged can cause them to prolifer- the level of IL-2 declines, which induces THl cells and Ctls ate and differentiate into active Ctls. Additionally, thl can to undergo programmed cell death by apoptosis. In this way, induce the up-regulation of co-stimulatory molecules on theis particularly true of memory CTL-Ps, which have lower activation requirements than naive cells do (Figure 14-2a). In general, though, most activated CTL-Ps require addi￾tional IL-2 produced by proliferating TH1 cells to proliferate and differentiate into effector CTLs. The fact that the IL-2 receptor is not expressed until after a CTL-P has been acti￾vated by antigen plus a class I MHC molecule favors the clonal expansion and acquisition of cytotoxicity by only the antigen-specific CTL-Ps. The proliferation and differentiation of both antigen￾activated TH1 cells and CTL-Ps depend on IL-2. In IL-2 knockout mice, the absence of IL-2 has been shown to abol￾ish CTL-mediated cytotoxicity. After clearance of antigen, the level of IL-2 declines, which induces TH1 cells and CTLs to undergo programmed cell death by apoptosis. In this way, the immune response is rapidly terminated, lessening the likelihood of nonspecific tissue damage from the inflamma￾tory response. The role of TH1 cells in the generation of CTLs from naive CTL-Ps is not completely understood, and it is unlikely that a TH1 cell and CTL-P interact directly. However, IL-2 and co￾stimulation are important in the transformation of naive CTL-Ps into effector cells, and TH1 cells can be mediators in the provision of these essential requirements. As shown in Figure 14-2b, the interaction of helper cells with antigen￾presenting cells can result in production of IL-2 by the TH1 cell. The paracrine action of this cytokine on nearby naive CTL-Ps whose TCRs are engaged can cause them to prolifer￾ate and differentiate into active CTLs. Additionally, TH1 can induce the up-regulation of co-stimulatory molecules on the 322 PART III Immune Effector Mechanisms IL-2 APC Class II MHC + antigen CD4 IL-2R TH1 cell TH1 cell TH1 cell IL-2 Co-stimulatory signal Activation Proliferation, differentiation Target cell CTL-P CD8 CTL Class I MHC + antigen IL-2R CD3 Ag-activated CTL-P Co-stimulatory signal IL-2R expression Proliferation Effector cytotoxic function – + – – + IL-2 expression – + + – – ± ± FIGURE 14-1 Generation of effector CTLs. Upon interaction with antigen–class I MHC complexes on appropriate target cells, CTL-Ps be￾gin to express IL-2 receptors (IL-2R) and lesser amounts of IL-2. Prolif￾eration and differentiation of antigen-activated CTL-Ps generally require additional IL-2 secreted by TH1 cells resulting from antigen activation and proliferation of CD4+ T cells. In the subsequent effector phase, CTLs destroy specific target cells