9536ach10221-2478/28/023:58 PM Page234mac76mac76:3854 234 RT II Generation of B-Cell and T-Cell Responses mediated signals CD28 is expressed by both YYYYY resting and activated T cells ↓↓A Ras-GDP CD28 TP P GEFs Ras-GDP GDP TH cell MEK MAP CTLA- Cytoplasm kinase MAP kinase CTLA-4 is expressed Both B7 molecules are on activated T cells expressed on dendritic cells, activated macrophages, and activated B cell FIGURE10-13TH-Cell activation requires a co-stimulatory signal provided by antigen-presenting cells (APCs). Interaction of B7 family members on APCs with CD28 delivers the costimulatory signal. En gagement of the closely related CTLA-4 molecule with B7 produces an inhibitory signal. All of these molecules contain at least one im- munoglobulin-like domain and thus belong to the immunoglobulin superfamily. (Adapted from P. S. Linsley and). A. Ledbetter, 1993. Annu. Rev. Immunol. 11: 191 1 tectable within 24 hours of stimulation with maximal ex- pression within 2 or 3 days post-stimulation. Even though the peak surface levels of CTLA-4 are lower than those of CD28, it still competes favorably for B7 molecules because it has a significantly higher avidity for these molecules than AP-1 CD28 does. Interestingly, the level of CTLA-4 expression is increased by CD28-generated co-stimulatory signals. Thi o Transcriptional provides regulatory braking via CTLA-4 in proportion to the cceleration received from CD28. Some of the importance of CTLA-4 in the regulation of lymphocyte activation and pro liferation is revealed by experiments with CTLA-4 knockout FIGURE 10-12 Activation of the small G protein, Ras. Signals from mice. T cells in these mice proliferate massively, which leads the T-cell receptor result in activation of Ras via the action of specifi nucleotide exchange factors(GEFs)that catalyze the ex- renomegaly (enlarged spleen), and death at 3 to 4 weeks change of GDP for GTP. Active Ras causes a cascade of reactions after birth. Clearly, the production of inhibitory signals by that result in the increased production of the transcription factor Fos. engagement of CTLA-4 is important in lymphocyte home Following their phosphorylation, Fos and Jun dimerize to yield the stasis CTLA-4 can effectively block CD28 Co-stimulation by transcription factor AP-1. Note that all these pathways have impor. competitive inhibition at the B7 binding site, an ability that ise for clinical use in autoimmune diseases and transplantation. As shown in Figure 10-14, an ingeniously CD28 delivers a positive co-stimulatory signal to the T cell; engineered chimeric molecule has been designed to explore signaling through CTLA-4 is inhibitory and down-regulates the therapeutic potential of CTLA-4. The Fc portion of the activation of the T cell CD28 is expressed by both resting human IgG has been fused to the B7-binding domain of and activated T cells, but CTLA-4 is virtually undetectable on CTLA-4 to produce a chimeric molecule called CTLA-4lg resting cells. Typically, engagement of the TCR causes the in- The human Fc region endows the molecule with a longer duction of CTLA-4 expression, and CTLA-4 is readily de- half-life in the body and the presence of B7 binding domainsCD28 delivers a positive co-stimulatory signal to the T cell; signaling through CTLA-4 is inhibitory and down-regulates the activation of the T cell. CD28 is expressed by both resting and activated T cells, but CTLA-4 is virtually undetectable on resting cells. Typically, engagement of the TCR causes the in￾duction of CTLA-4 expression, and CTLA-4 is readily de- 234 PART II Generation of B-Cell and T-Cell Responses FIGURE 10-13 TH-cell activation requires a co-stimulatory signal provided by antigen-presenting cells (APCs). Interaction of B7 family members on APCs with CD28 delivers the co-stimulatory signal. En￾gagement of the closely related CTLA-4 molecule with B7 produces an inhibitory signal. All of these molecules contain at least one im￾munoglobulin-liké domain and thus belong to the immunoglobulin superfamily. [Adapted from P. S. Linsley and J. A. Ledbetter, 1993, Annu. Rev. Immunol. 11:191.] FIGURE 10-12 Activation of the small G protein, Ras. Signals from the T-cell receptor result in activation of Ras via the action of specific guanine nucleotide exchange factors (GEFs) that catalyze the ex￾change of GDP for GTP. Active Ras causes a cascade of reactions that result in the increased production of the transcription factor Fos. Following their phosphorylation, Fos and Jun dimerize to yield the transcription factor AP-1. Note that all these pathways have impor￾tant effects other than the specific examples shown in the figure. Cytoplasm MAP kinase pathway Nucleus + + Pi Ras-GDP (inactive) Ras-GDP (active) P P P P P GTP GDP TCR-mediated signals Raf MEK MAP kinase GEFs Elk Elk Jun AP-1 Jun Fos Fos Fos Transcriptional activation of several genes S S S S S S S S S S S S S S S S B7 S S S S B7 TH cell CD28 is expressed by both resting and activated T cells CTLA-4 APC Both B7 molecules are expressed on dendritic cells, activated macrophages, and activated B cells CD28 CTLA-4 is expressed on activated T cells tectable within 24 hours of stimulation, with maximal ex￾pression within 2 or 3 days post-stimulation. Even though the peak surface levels of CTLA-4 are lower than those of CD28, it still competes favorably for B7 molecules because it has a significantly higher avidity for these molecules than CD28 does. Interestingly, the level of CTLA-4 expression is increased by CD28-generated co-stimulatory signals. This provides regulatory braking via CTLA-4 in proportion to the acceleration received from CD28. Some of the importance of CTLA-4 in the regulation of lymphocyte activation and pro￾liferation is revealed by experiments with CTLA-4 knockout mice. T cells in these mice proliferate massively, which leads to lymphadenopathy (greatly enlarged lymph nodes), splenomegaly (enlarged spleen), and death at 3 to 4 weeks after birth. Clearly, the production of inhibitory signals by engagement of CTLA-4 is important in lymphocyte home￾ostasis. CTLA-4 can effectively block CD28 co-stimulation by competitive inhibition at the B7 binding site, an ability that holds promise for clinical use in autoimmune diseases and transplantation. As shown in Figure 10-14, an ingeniously engineered chimeric molecule has been designed to explore the therapeutic potential of CTLA-4. The Fc portion of human IgG has been fused to the B7-binding domain of CTLA-4 to produce a chimeric molecule called CTLA-4Ig. The human Fc region endows the molecule with a longer half-life in the body and the presence of B7 binding domains 8536d_ch10_221-247 8/28/02 3:58 PM Page 234 mac76 mac76:385_reb: