8536dch10221-2478/28/023:58 PM Page233mac76mac76:385As T-Cell Maturation. Activation, and Differentiation cHAPTER 10 233 (a) YYYYYYB8Y IKB/NF-KB ATP ATP ADP →IB (acti (inactive) ZAP-70 →NFKB (C) FIGURE Signal-transduction path- ways associated with T-cell activation (a) Phospholipase Cy(PLC) is activated by Intracellular phosphorylation. Active PLC hydrolyzes a Ca-t stores Calmodulin-- phospholipid component of the plasma Calmodulin membrane to generate the second mes- engers, DAG and IP3.(b) Protein kinase C Calcineurin. (PKO is activated by DAG and Ca calmodulin-Ca'+ Among the numerous effects of PKC is (active) phosphorylation of IkB, a cytoplasmic pro- tein that binds the transcription factor NF NFAT KB and prevents it from entering the nucleus. Phosphorylation of lkB releases F-KB. which then translocates into the ucleus.(c) Ca+-dependent activation of calcineurin. Calcineurin is a Ca /calmod ulin dependent phosphatase. IP3 mediates the release of Ca" from the endoplasmic NFAT NF-KB reticulum Ca" binds the protein calmed ulin which then associates with and acti. ates the Ca*/calmodulin-dependent phosphatase calcineurin. Active calcin urin removes a phosphate group from Transcriptional activation NFAT, which allows this transcription fac- tor to translocate into the nucleus ERK), allows it to activate Elk, a transcription factor neces- A subsequent antigen-nonspecific co-stimulatory signal sary for the expression of Fos. Phosphorylation of Fos b signal 2, is provided primarily by interactions between MAP kinase allows it to associate with Jun to form AP-1 CD28 on the T cell and members of the B7 family on which is an essential transcription factor for T-cell activation the apc There are two related forms of B7, B7-1 and B7-2( Figure 10-13). These molecules are members of the immunoglobu Co-Stimulatory Signals Are Required superfamily and have a similar organization of extracel for Full T-Cell Activation lular domains but markedly different cytosolic domains. Both B7 molecules are constitutively expressed on dendritic T-cell activation requires the dynamic interaction of multiple cells and induced on activated macrophages and activated B membrane molecules described above, but this interaction, cells. The ligands for B7 are CD28 and CTLA-4(also known by itself, is not sufficient to fully activate naration and subse. as CD152), both of which are expressed on the T-cell mem- ve t cells. Naiv T cells require more than one signal for acti quent proliferation into effector cells brane as disulfide- linked homodimers; like B7, they are members of the immunoglobulin superfamily( Figure Signal I, the initial signal, is generated by interaction of 10-13). Although CD28 and CTLA-4 are structurally similar an antigenic peptide with the TCR-CD3 comple lycoproteins, they act antagonistically. Signaling throughERK), allows it to activate Elk, a transcription factor neces￾sary for the expression of Fos. Phosphorylation of Fos by MAP kinase allows it to associate with Jun to form AP-1, which is an essential transcription factor for T-cell activation. Co-Stimulatory Signals Are Required for Full T-Cell Activation T-cell activation requires the dynamic interaction of multiple membrane molecules described above, but this interaction, by itself, is not sufficient to fully activate naive T cells. Naive T cells require more than one signal for activation and subse￾quent proliferation into effector cells: ■ Signal 1, the initial signal, is generated by interaction of an antigenic peptide with the TCR-CD3 complex. T-Cell Maturation, Activation, and Differentiation CHAPTER 10 233 ■ A subsequent antigen-nonspecific co-stimulatory signal, signal 2, is provided primarily by interactions between CD28 on the T cell and members of the B7 family on the APC. There are two related forms of B7, B7-1 and B7-2 (Figure 10-13). These molecules are members of the immunoglobu￾lin superfamily and have a similar organization of extracel￾lular domains but markedly different cytosolic domains. Both B7 molecules are constitutively expressed on dendritic cells and induced on activated macrophages and activated B cells. The ligands for B7 are CD28 and CTLA-4 (also known as CD152), both of which are expressed on the T-cell mem￾brane as disulfide-linked homodimers; like B7, they are members of the immunoglobulin superfamily (Figure 10-13). Although CD28 and CTLA-4 are structurally similar glycoproteins, they act antagonistically. Signaling through FIGURE 10-11 Signal-transduction path￾ways associated with T-cell activation. (a) Phospholipase C (PLC) is activated by phosphorylation. Active PLC hydrolyzes a phospholipid component of the plasma membrane to generate the second mes￾sengers, DAG and IP3. (b) Protein kinase C (PKC) is activated by DAG and Ca2. Among the numerous effects of PKC is phosphorylation of IkB, a cytoplasmic pro￾tein that binds the transcription factor NF- B and prevents it from entering the nucleus. Phosphorylation of IkB releases NF-B, which then translocates into the nucleus. (c) Ca2-dependent activation of calcineurin. Calcineurin is a Ca2/calmod￾ulin dependent phosphatase. IP3 mediates the release of Ca2 from the endoplasmic reticulum. Ca2 binds the protein calmod￾ulin, which then associates with and acti￾vates the Ca2/calmodulin-dependent phosphatase calcineurin. Active calcine￾urin removes a phosphate group from NFAT, which allows this transcription fac￾tor to translocate into the nucleus. DAG Cytoplasm Nucleus IP3 Intracellular Ca2+ stores IκB/NF-κB NF-κB NF-κB IκB Phospho￾lipase Cγ (inactive) PKC (active) ATP ADP ATP ADP ZAP-70 + + + Ca2+ Calmodulin-Ca2+ Calcineurin￾calmodulin-Ca2+ (active) Calcineurin Calmodulin (inactive) NFAT NFAT Transcriptional activation of several genes NFAT P P P P (c) (a) (b) 8536d_ch10_221-247 8/28/02 3:58 PM Page 233 mac76 mac76:385_reb: