8536ach1022-2478/28/023:58 PM Page229mac76mac76:3854 T-Cell Matur INSTRUCTIVE MODEL CD4+8 D8 E-◎ CDiloghi CD4-8+T cell STOCHASTIC MODEL g+ class I MHC CD4 CD4+8+ CLogh Ag+ class I MHC Apoptosis of the CD4 and CD8 coreceptors in thymic se- lection of double positive thymocytes leading single positive T cells. According to the Able to bind structive model, interaction of one coreceptor Ag+ class II MHC with MHC molecules on stromal cells results Random CD4+8-Tcell in down-regulation of the other coreceptor. Not able to bind According to the stochastic model, down Ag class II MHC → Apoptosis regulation of CD4 or CD8 is a random process (Figure 10-9). The instructional model postulates that the and differentiating into memory cells or effector cells. Many multiple interactions between the TCR, CD8 or CD4 of the gene products that appear upon interaction with anti coreceptors, and class I or class II MHC molecules instruct gen can be grouped into one of three categories depending the cells to differentiate into either CD8 or CD4 single- on how early they can be detected after antigen recognition positive cells, respectively. This model would predict that a ( Table 10-2) class I MHC-specific TCR together with the CD8 would generate a signal that is different from the signal in-. Immediate genes, expressed within half an hour of duced by a class II MHC-specific TCR together with the tigen recognition, encode a number of transcription CD4 coreceptor. The stochastic model suggests that CD4 or factors, including c-Fos, c-Myc, c-Jun, NFAT, and NF-KB CD8 expression is switched off randomly with no relation to Early genes, expressed within 1-2 h of antigen the specificity of the TCR. Only those thymocytes whose recognition, encode IL-2, IL-2R(IL-2 receptor), IL-3, TCR and remaining coreceptor recognize the same class of IL-6, IFN-Y, and numerous other proteins MHC molecule will mature At present, it is not possible to. Late genes, expressed more than 2 days after antigen choose one model over the other recognition, encode various adhesion molecules These profound changes are the result of signal-transduction TH-Cell Activation pathways that are activated by the encounter between the TCR and MHC-peptide complexes. An overview of some of The central event in the generation of both humoral and cell- the basic strategies of cellular signaling will be useful back pansion of TH cells. Activation of Tc cells, which is generally by T cells. preciating the specific signaling pathways used mediated immune responses is the activation and clonal ex- ground for app similar to TH-cell activation, is described in Chapter 14.TH- cell activation is initiated by interaction of the TCR-CD3 Signal-Transduction Pathways Have Several mplex with a processed antigenic peptide bound to a class Features in Common II MHC molecule on the surface of an antigen-presenting cell. This interaction and the resulting activating signals also The detection and interpretation of signals from the environ involve various accessory membrane molecules on the TH ment is an indispensable feature of all cells, including those of cell and the an tigen -presenting c ell. Interaction of a TH cell the immune system. Although there are an enormous number with antigen initiates a cascade of biochemical events that in- of different signal-transduction pathways, some common duces the resting TH cell to enter the cell cycle, proliferating themes are typical of these crucial integrative processes(Figure 10-9). The instructional model postulates that the multiple interactions between the TCR, CD8 or CD4 coreceptors, and class I or class II MHC molecules instruct the cells to differentiate into either CD8 or CD4 single￾positive cells, respectively. This model would predict that a class I MHC–specific TCR together with the CD8 coreceptor would generate a signal that is different from the signal in￾duced by a class II MHC–specific TCR together with the CD4 coreceptor. The stochastic model suggests that CD4 or CD8 expression is switched off randomly with no relation to the specificity of the TCR. Only those thymocytes whose TCR and remaining coreceptor recognize the same class of MHC molecule will mature. At present, it is not possible to choose one model over the other. TH-Cell Activation The central event in the generation of both humoral and cell￾mediated immune responses is the activation and clonal ex￾pansion of TH cells. Activation of TC cells, which is generally similar to TH-cell activation, is described in Chapter 14. TH￾cell activation is initiated by interaction of the TCR-CD3 complex with a processed antigenic peptide bound to a class II MHC molecule on the surface of an antigen-presenting cell. This interaction and the resulting activating signals also involve various accessory membrane molecules on the TH cell and the antigen-presenting cell. Interaction of a TH cell with antigen initiates a cascade of biochemical events that in￾duces the resting TH cell to enter the cell cycle, proliferating and differentiating into memory cells or effector cells. Many of the gene products that appear upon interaction with anti￾gen can be grouped into one of three categories depending on how early they can be detected after antigen recognition (Table 10-2): ■ Immediate genes, expressed within half an hour of antigen recognition, encode a number of transcription factors, including c-Fos, c-Myc, c-Jun, NFAT, and NF-B ■ Early genes, expressed within 1–2 h of antigen recognition, encode IL-2, IL-2R (IL-2 receptor), IL-3, IL-6, IFN-, and numerous other proteins ■ Late genes, expressed more than 2 days after antigen recognition, encode various adhesion molecules These profound changes are the result of signal-transduction pathways that are activated by the encounter between the TCR and MHC-peptide complexes. An overview of some of the basic strategies of cellular signaling will be useful back￾ground for appreciating the specific signaling pathways used by T cells. Signal-Transduction Pathways Have Several Features in Common The detection and interpretation of signals from the environ￾ment is an indispensable feature of all cells, including those of the immune system. Although there are an enormous number of different signal-transduction pathways, some common themes are typical of these crucial integrative processes: T-Cell Maturation, Activation, and Differentiation CHAPTER 10 229 FIGURE 10-9 Proposed models for the role of the CD4 and CD8 coreceptors in thymic se￾lection of double positive thymocytes leading to single positive T cells. According to the in￾structive model, interaction of one coreceptor with MHC molecules on stromal cells results in down-regulation of the other coreceptor. According to the stochastic model, down￾regulation of CD4 or CD8 is a random process. INSTRUCTIVE MODEL CD8 engagement signal CD4 engagement signal STOCHASTIC MODEL CD4lo8hi CD4hi8lo CD4+8+ CD4+8+ CD4lo8hi CD4hi8lo Random CD4 Random CD8 CD4+8+ CD4+8+ CD4−8+ T cell CD4+8− T cell CD4−8+ T cell Able to bind Ag + class I MHC Able to bind Ag + class II MHC Not able to bind Ag + class II MHC Not able to bind Ag + class I MHC Apoptosis CD4+8− T cell Apoptosis 8536d_ch10_221-247 8/28/02 3:58 PM Page 229 mac76 mac76:385_reb: