《免疫学》（英文版） Chapter 10 T-Cell Maturation Activation, and Differentiation

9536d_ch102212478/28/023:58 PM Page226mac76ma76:385e 226 RT II Generation of B-Cell and T-Cell Respons TABLE10·1 Effect of class I or lI MHC deficiency tured in vitro with antigen-presenting cells expressing the on thymocyte populations H-Y antigen, the thymocytes were observed to undergo apoptosis, providing a striking example of negative selection KNOCKOUT MICE Some Central Issues in Thymic Sel Class I Class ll Cell type deficient deficient Remain Unresolved Although a great deal has been learned about the develop CD4 CD mental processes that generate mature CD4 and CD8 T CD4+CD8+ cells, some mysteries persist. Prominent among them is a seeming paradox: If positive selection allows only thymo CD8 cytes reactive with self-MHC molecules to survive, and nega- Plus sign indicates normal distribution of indicated cell types in thymus cytes, then no T cells would be allowed to mature. Since this Minus sign indicates absence of cell type. is not the outcome of T-cell development, clearly, other fac tors operate to prevent these two MHC-dependent processes from eliminating the entire repertoire of MHC-restricted T one with the H-2 haplotype and one with the H Experimental evidence from fetal thymic organ culture type(Figure 10-6). Since the receptor transgenes (FTOC)has been helpful in resolving this puzzle. In this sy ready rearranged, other TCR-gene rearrangement tem, mouse thymic lobes are excised at a gestational age of day suppressed in the transgenic mice; therefore, a high percent- 16 and placed in culture. At this time, the lobes consist pre- age of the thymocytes in the transgenic mice expressed the dominantly of CD48 thymocytes. Because these immature, T-cell receptor encoded by the transgene. Thymocytes double-negative thymocytes continue to develop in the organ expressing the TCR transgene were found to mature into culture, thymic selection can be studied under conditions that CD8* T cells only in the transgenic mice with the H-2 class permit a range of informative experiments. Particular use has I MHC haplotype (i.e, the haplotype for which the transgene receptor was restricted). In transgenic mice with a different CD8 IHC haplotype(H-2), immature, double-positive thyme tes expressing the transgene were present, but these thy Influenza. oocytes failed to mature into CD8 T cells. These findings infected ≈○ clone confirmed that interaction between T-cell receptors on im mature thymocytes and self-MHC molecules is required for Class I mhc ositive selection In the absence of self-mHc molecules,as (H2) in the H-2 transgenic mice, positive selection and subse aB-TCR genes quent maturation do not occur Evidence for deletion of thymocytes reactive with self- antigen plus MHC molecules comes from a number of ex perimental systems. In one system, thymocyte maturation was analyzed in transgenic mice bearing an aB TCR trans- gene specific for the class I D MHC molecule plus H-Y anti- gen, a small protein that is encoded on the Y chromosome Thymocytes transgenic transgenic and is therefore a self-molecule only in male mice. In this periment, the MHC haplotype of the transgenic mice was In transgenics H-2, the same as the MHC restriction of the transgene- TCR*/CD4+8* encoded receptor. Therefore any differences in the selection TCR+/CD8+ of thymocytes in male and female transgenics would be re- lated to the presence or absence of H-Y antigen. FIGURE 10-6Effect of host haplotype on T-cell maturation in mice Analysis of thymocytes in the transgenic mice revealed carrying transgenes encoding an H-2 class I-restricted T-cell recep that female mice contained thymocytes expressing the H-Y- tor specific for influenza virus. The presence of the rearranged TCR ecific TCR transgene, but male mice did not(Figure 10-7). transgenes suppressed other gene rearrangements in the transgen- In other words, H-Y-reactive thymocytes were self-reactive ics; therefore, most of the thymocytes in the transgenics expressed in the male mice and were eliminated. However, in the female the aB T-cell receptor encoded by the transgene Immature double- ansgenics, which did not express the H-Y antigen, these positive thymocytes matured into CD8* T cells only in transgenics cells were not self-reactive and thus were not eliminated. with the haplotype(H-2)corresponding to the MHC restriction of When thymocytes from these male transgenic mice were cul- the TCR transgene

one with the H-2k haplotype and one with the H-2d haplo￾type (Figure 10-6). Since the receptor transgenes were al￾ready rearranged, other TCR-gene rearrangements were suppressed in the transgenic mice; therefore, a high percent￾age of the thymocytes in the transgenic mice expressed the T-cell receptor encoded by the transgene. Thymocytes expressing the TCR transgene were found to mature into CD8 T cells only in the transgenic mice with the H-2k class I MHC haplotype (i.e., the haplotype for which the transgene receptor was restricted). In transgenic mice with a different MHC haplotype (H-2d ), immature, double-positive thymo￾cytes expressing the transgene were present, but these thy￾mocytes failed to mature into CD8 T cells. These findings confirmed that interaction between T-cell receptors on im￾mature thymocytes and self-MHC molecules is required for positive selection. In the absence of self-MHC molecules, as in the H-2d transgenic mice, positive selection and subse￾quent maturation do not occur. Evidence for deletion of thymocytes reactive with self￾antigen plus MHC molecules comes from a number of ex￾perimental systems. In one system, thymocyte maturation was analyzed in transgenic mice bearing an  TCR trans￾gene specific for the class I Db MHC molecule plus H-Y anti￾gen, a small protein that is encoded on the Y chromosome and is therefore a self-molecule only in male mice. In this ex￾periment, the MHC haplotype of the transgenic mice was H-2b , the same as the MHC restriction of the transgene￾encoded receptor. Therefore any differences in the selection of thymocytes in male and female transgenics would be re￾lated to the presence or absence of H-Y antigen. Analysis of thymocytes in the transgenic mice revealed that female mice contained thymocytes expressing the H-Y– specific TCR transgene, but male mice did not (Figure 10-7). In other words, H-Y–reactive thymocytes were self-reactive in the male mice and were eliminated. However, in the female transgenics, which did not express the H-Y antigen, these cells were not self-reactive and thus were not eliminated. When thymocytes from these male transgenic mice were cul￾tured in vitro with antigen-presenting cells expressing the H-Y antigen, the thymocytes were observed to undergo apoptosis, providing a striking example of negative selection. Some Central Issues in Thymic Selection Remain Unresolved Although a great deal has been learned about the develop￾mental processes that generate mature CD4 and CD8 T cells, some mysteries persist. Prominent among them is a seeming paradox: If positive selection allows only thymo￾cytes reactive with self-MHC molecules to survive, and nega￾tive selection eliminates the self-MHC–reactive thymo￾cytes, then no T cells would be allowed to mature. Since this is not the outcome of T-cell development, clearly, other fac￾tors operate to prevent these two MHC-dependent processes from eliminating the entire repertoire of MHC-restricted T cells. Experimental evidence from fetal thymic organ culture (FTOC) has been helpful in resolving this puzzle. In this sys￾tem, mouse thymic lobes are excised at a gestational age of day 16 and placed in culture. At this time, the lobes consist pre￾dominantly of CD48 thymocytes. Because these immature, double-negative thymocytes continue to develop in the organ culture, thymic selection can be studied under conditions that permit a range of informative experiments. Particular use has 226 PART II Generation of B-Cell and T-Cell Responses TABLE 10-1 Effect of class I or II MHC deficiency on thymocyte populations* KNOCKOUT MICE Control Class I Class II Cell type mice deficient deficient CD4CD8   CD4CD8   CD4   CD8   * Plus sign indicates normal distribution of indicated cell types in thymus. Minus sign indicates absence of cell type. FIGURE 10-6 Effect of host haplotype on T-cell maturation in mice carrying transgenes encoding an H-2b class I–restricted T-cell recep￾tor specific for influenza virus. The presence of the rearranged TCR transgenes suppressed other gene rearrangements in the transgen￾ics; therefore, most of the thymocytes in the transgenics expressed the  T-cell receptor encoded by the transgene. Immature double￾positive thymocytes matured into CD8 T cells only in transgenics with the haplotype (H-2k ) corresponding to the MHC restriction of the TCR transgene. Thymocytes in transgenics TCR+/CD4+8+ TCR+/CD8+ H–2k transgenic + + + − Influenza￾infected target cell TC-cell clone (H-2k) CD8 Class I MHC (H-2k) αβ-TCR genes H–2d transgenic 8536d_ch10_221-247 8/28/02 3:58 PM Page 226 mac76 mac76:385_reb:

9536d_ch102212478/28/023:58 PM Page227mac76ma76:385e T-Cell Matur CTL H-Y specific H-2Db restricted peptic Clone TCR Male cell(H-2D) a and B genes Female cell(H-2Db) Use to make a H-Y TCR transgenic mice FIGURE 10-7Experimental demonstration that gative selection of thymocyte gen plus self-MHC. In this experiment, H-2male and female prepared carrying transgenes specific for H-Y antigen plus the D" mol Male h-2Db Female h-2Db ecule. This antigen is expressed only in males. FACS analysis of thymocytes from the transgenics showed that mature CD8" T cells expressing the transgene Thymocytes were absent in the male mice but present in the fe- CD4-8 male mice, suggesting that thymocytes reactive with CD4+8+ a self-antigen(in this case, H-Y antigen in the male mice)are deleted during thymic selection [ Adapted from H won Boehmer and P. Kisielow, 1990, Science CDSt 248:1370 been made of mice in which the peptide transporter, TAP-1, concentrations of peptide. At low peptide concentrations, has been knocked out. In the absence of TAP-1, only low levels few MHC molecules bound peptide and the avidity of the of MHC class I are expressed on thymic cells, and the develop- TCR-MHC interaction was low. As peptide concentrations ment of CD8* thymocytes is blocked. However, when exoge- were raised, the number of peptide-MHC complexes dis- nous peptides are added to these organ cultures, then played increased and so did the avidity of the interaction. In peptide-bearing class I MHC molecules appear on the surface this experiment, very few CD8 cells appeared when peptide of the thymic cells, and development of CD8* T cells is re- was not added, but even low concentrations of the relevant stored. Significantly, when a diverse peptide mixture is added, peptide resulted in the appearance of significant numbers of the extent of CD8 T-cell restoration is greater than when a CD8 T cells bearing the transgenic TCR receptor. Increas- ingle peptide is added. This indicates that the role of peptide ing the peptide concentrations to an optimum range yielded is not simply to support stable MHC expression but also to be the highest number of CD8 T cells. However, at higher con recognized itself in the selection process centrations of peptide, the numbers of CD8 T cells pro- q Two competing hypotheses attempt to explain the Para- duced declined steeply. The results of these experiments dox of MHC-dependent positive and negative selection. The show that positive and negative selection can be achieved avidity hypothesis asserts that differences in the strength of with signals generated by the same peptide-MHC combina- the signals received by thymocytes undergoing positive and tion. No signal (no peptide) fails to support positive selec negative selection determine the outcome, with signal tion. A weak signal (low peptide level)induces positive strength dictated by the avidity of the TCR-MHC-peptide in- selection. However, too strong a signal(high peptide level) teraction. The differential-signaling hypothesis holds that the results in negative selection outcomes of selection are dictated by different signals, rather The differential-signaling model provides an alternative than different strengths of the same signal explanation for determining whether a T cell undergoes posi- The avidity hypothesis was tested with TAP-1 knockout tive or negative selection. This model is a qualitative rather mice transgenic for an aB TCR that recognized an LCM virus than a quantitative one, and it emphasizes the nature of the peptide-MHC complex. These mice were used to prepare fe- signal delivered by the TCR rather than its strength. At tal thymic organ cultures(Figure 10-8). The avidity of the core of this model is the observation that some MHC-peptide TCR-MHC interaction was varied by the use of different complexes can deliver only a weak or partly activating signal

been made of mice in which the peptide transporter, TAP-1, has been knocked out. In the absence of TAP-1, only low levels of MHC class I are expressed on thymic cells, and the develop￾ment of CD8 thymocytes is blocked. However, when exoge￾nous peptides are added to these organ cultures, then peptide-bearing class I MHC molecules appear on the surface of the thymic cells, and development of CD8 T cells is re￾stored. Significantly, when a diverse peptide mixture is added, the extent of CD8 T-cell restoration is greater than when a single peptide is added. This indicates that the role of peptide is not simply to support stable MHC expression but also to be recognized itself in the selection process. Two competing hypotheses attempt to explain the para￾dox of MHC-dependent positive and negative selection. The avidity hypothesis asserts that differences in the strength of the signals received by thymocytes undergoing positive and negative selection determine the outcome, with signal strength dictated by the avidity of the TCR-MHC-peptide in￾teraction. The differential-signaling hypothesis holds that the outcomes of selection are dictated by different signals, rather than different strengths of the same signal. The avidity hypothesis was tested with TAP-1 knockout mice transgenic for an  TCR that recognized an LCM virus peptide-MHC complex. These mice were used to prepare fe￾tal thymic organ cultures (Figure 10-8). The avidity of the TCR-MHC interaction was varied by the use of different concentrations of peptide. At low peptide concentrations, few MHC molecules bound peptide and the avidity of the TCR-MHC interaction was low. As peptide concentrations were raised, the number of peptide-MHC complexes dis￾played increased and so did the avidity of the interaction. In this experiment, very few CD8 cells appeared when peptide was not added, but even low concentrations of the relevant peptide resulted in the appearance of significant numbers of CD8 T cells bearing the transgenic TCR receptor. Increas￾ing the peptide concentrations to an optimum range yielded the highest number of CD8 T cells. However, at higher con￾centrations of peptide, the numbers of CD8 T cells pro￾duced declined steeply. The results of these experiments show that positive and negative selection can be achieved with signals generated by the same peptide-MHC combina￾tion. No signal (no peptide) fails to support positive selec￾tion. A weak signal (low peptide level) induces positive selection. However, too strong a signal (high peptide level) results in negative selection. The differential-signaling model provides an alternative explanation for determining whether a T cell undergoes posi￾tive or negative selection. This model is a qualitative rather than a quantitative one, and it emphasizes the nature of the signal delivered by the TCR rather than its strength. At the core of this model is the observation that some MHC-peptide complexes can deliver only a weak or partly activating signal T-Cell Maturation, Activation, and Differentiation CHAPTER 10 227 FIGURE 10-7 Experimental demonstration that negative selection of thymocytes requires self-anti￾gen plus self-MHC. In this experiment, H-2b male and female transgenics were prepared carrying TCR transgenes specific for H-Y antigen plus the Db mol￾ecule. This antigen is expressed only in males. FACS analysis of thymocytes from the transgenics showed that mature CD8 T cells expressing the transgene were absent in the male mice but present in the fe￾male mice, suggesting that thymocytes reactive with a self-antigen (in this case, H-Y antigen in the male mice) are deleted during thymic selection. [Adapted from H. von Boehmer and P. Kisielow, 1990, Science 248:1370.] Use to make α H-Y TCR transgenic mice Male H-2Db Female H-2Db H-Y expression Thymocytes CD4−8− CD4+8+ CD4+ CD8+ + + + + + − − + + + + + + Clone TCR α and β genes Female cell (H-2Db Male cell (H-2D ) b) CTL H-Y specific H-2Db restricted H-Y peptide α β × 8536d_ch10_221-247 8/28/02 3:58 PM Page 227 mac76 mac76:385_reb:

9536d_ch102212478/28/023:58 PM Page228mac76ma76:385e 228 PART 11 Generation of B-Cell and T-Cell Responses while others can deliver a complete signal. In this model, pos- pression was artificially raised to twice its normal level, the itive selection takes place when the TCRs of developing thy- concentration of mature CD8 cells in the thymus was one mocytes encounter MHC-peptide complexes that deliver thirteenth of the concentration in control mice bearing nor- weak or partial signals to their receptors, and negative selec- mal levels of CD8 on their surface. Since the interaction of T tion results when the signal is complete. At this point it is not cells with class I MHC molecules is strengthened by partici- ossible to decide between the avidity model and the differen- pation of CD8, perhaps the increased expression of CD tial-signaling model; both have experimental support. It may would increase the avidity of thymocytes for class I mole be that in some cases, one of these mechanisms operates to the cules, possibly making their negative selection more likely. complete exclusion of the other. It is also possible that no sin- Another important open question in thymic selection is gle mechanism accounts for all the outcomes in the cellular how double-positive thymocytes are directed to become ei- teractions that take place in the thymus and more than one ther CD4 8 or CD4 8 T cells. Selection of CD4 8 thy- mechanism may play a significant role. Further work is re- mocytes gives rise to class I MHC-restricted CD8 T cells quired to complete our understanding of this matter. and class II-restricted CD4+T cells. Two models have been The differential expression of the coreceptor CD8 also can proposed to explain the transformation of a double-positive ffect thymic selection. In an experiment in which CD8 ex- precursor into one of two different single-positive lineag (a) Experimental procedure-fetal thymic organ culture(FTOC) Place in Porous membrane Growth medium (b) Development of CDS* CD4- MHC I-restricted cell Thymocyte Degree of Thymus Thymic CD8+ T-cell FIGURE 10-8 Role of peptides in selection. donor peptide added development Thymuses harvested before their thymocyteNormal populations have undergone positive and negative selection allow study of the develop- ment and selection of single positive Norma CD4"CD8 and CD4" CD8T)T cells(a) Peptide Outline of the experimental procedure for in vitro fetal thymic organ culture(FTOC).(b) The development and selection ofTCR-transgenic CD8"CD4 class I-restricted T cells depends TAP.1 deficient on TCR peptide-MHC I interactions. TAP. None Minimal knockout mice are unable to form peptide- MHC complexes unless peptide is added The mice used in this study were transgenic for the a and B chains of a TCR that recog- Weak signal nizes the added peptide bound to MHC molecules of the TAP. knockout/TCR trans Approaches genic mice. Varying the amount of added pep- normal tide revealed that low concentrations of peptide, producing low avidity of binding, re- sulted in positive selection and nearly normal Strong signal levels of CD4"CD8" cells. High concentra- tions of peptide, producing high avidity of binding to the TCR, caused negative selection, Minimal and few CD4-CD8+ t cells (Adapted from Ashton Rickardt et al.(1994) e25:651

while others can deliver a complete signal. In this model, pos￾itive selection takes place when the TCRs of developing thy￾mocytes encounter MHC-peptide complexes that deliver weak or partial signals to their receptors, and negative selec￾tion results when the signal is complete. At this point it is not possible to decide between the avidity model and the differen￾tial-signaling model; both have experimental support. It may be that in some cases, one of these mechanisms operates to the complete exclusion of the other. It is also possible that no sin￾gle mechanism accounts for all the outcomes in the cellular interactions that take place in the thymus and more than one mechanism may play a significant role. Further work is re￾quired to complete our understanding of this matter. The differential expression of the coreceptor CD8 also can affect thymic selection. In an experiment in which CD8 ex￾pression was artificially raised to twice its normal level, the concentration of mature CD8 cells in the thymus was one￾thirteenth of the concentration in control mice bearing nor￾mal levels of CD8 on their surface. Since the interaction of T cells with class I MHC molecules is strengthened by partici￾pation of CD8, perhaps the increased expression of CD8 would increase the avidity of thymocytes for class I mole￾cules, possibly making their negative selection more likely. Another important open question in thymic selection is how double-positive thymocytes are directed to become ei￾ther CD48 or CD48 T cells. Selection of CD48 thy￾mocytes gives rise to class I MHC–restricted CD8 T cells and class II–restricted CD4 T cells. Two models have been proposed to explain the transformation of a double-positive precursor into one of two different single-positive lineages 228 PART II Generation of B-Cell and T-Cell Responses FIGURE 10-8 Role of peptides in selection. Thymuses harvested before their thymocyte populations have undergone positive and negative selection allow study of the develop￾ment and selection of single positive (CD4CD8 and CD4CD8) T cells. (a) Outline of the experimental procedure for in vitro fetal thymic organ culture (FTOC). (b) The development and selection of CD8CD4 class I–restricted T cells depends on TCR peptide-MHC I interactions. TAP-1 knockout mice are unable to form peptide￾MHC complexes unless peptide is added. The mice used in this study were transgenic for the  and  chains of a TCR that recog￾nizes the added peptide bound to MHC I molecules of the TAP-1 knockout/TCR trans￾genic mice. Varying the amount of added pep￾tide revealed that low concentrations of peptide, producing low avidity of binding, re￾sulted in positive selection and nearly normal levels of CD4CD8 cells. High concentra￾tions of peptide, producing high avidity of binding to the TCR, caused negative selection, and few CD4CD8 T cells appeared. [Adapted from Ashton Rickardt et al. (1994) Cell 25:651.] (a) Experimental procedure—fetal thymic organ culture (FTOC) (b) Development of CD8+ CD4− MHC I–restricted cells Thymus donor Amount of peptide added Thymocyte Thymic stromal cell Degree of CD8+ T-cell development None Peptide Normal None Minimal Optimal Approaches normal High Minimal Remove thymus Place in FTOC Porous membrane Growth medium Normal TCR-transgenic TAP-1 deficient Weak signal No signal Weak signal Strong signal 8536d_ch10_221-247 8/28/02 3:58 PM Page 228 mac76 mac76:385_reb:

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: