8536ach1022-2478/28/023:58 PM Page25mac76mac76:3854 T-Cell Maturation. Activation, and Differentiation CHAPTER 10 (a)CTLA-ilg CTLA-4 binding domain tokines, especially of IL-2 Anergy can also be induced by abating TH cells with normal APCs in the presence of the Fab portion of anti-CD28, which blocks the interaction of CD28 with B7( Figure 10-15b) Two different control experiments demonstrate that fixed APCs bearing appropriate peptide-MHC complexes can de- (b)B7 blockade by CTLA-ilg rer an effective signal mediated by T-cell receptors. In one experiment, T cells are incubated both with fixed APCs bear- TCR 一CD28 ing peptide-MHC complexes recognized by the TCR of the T T cell cells and with normal APCs, which express B7(Figure 10-15d). The fixed APCs engage the TCRs of the T cells,and he b7 molecules on the surface of the normal APCs cross- link the CD28 of the t cell. These t cells thus receive both signals and undergo activation. The addition of bivalent anti-CD28 to mixtures of fixed APCs and T cells also pro- ides effective co-stimulation by crosslinking CD28(Figure 10-15e). Well-controlled systems for studying anergy in vitro have stimulated considerable interest in this phenome- non. However, more work is needed to develop good animal FIGURE 10-14 CTLA-41g, a chimeric suppressor of co-stimulation. systems for establishing anergy and studying its role in vivo. (a)CTLA4lg, a genetically engineered molecule in which the Fc por ion of human Igg is joined to the B7-binding domain of CTLA-4 () CTLA-4Ig blocks costimulation by binding to B7 on antigen pre- Superantigens Induce T-Cell Activation by senting cells and preventing the binding of CD28, a major co-stimula. Binding the TCR and MHC lI Simultaneously ry molecule of T cells Superantigens are aneously to the Ve domain of a T-cell receptor and to the a chain of a class lI MHC molecule. Both exogenous and en- llows it to bind to B7. A promising clinical trial of CTLA-4 dogenous superantigens have been identified Crosslinkage has been conducted in patients with psoriasis vulgaris, a of a T-cell receptor and class II MHC molecule by either type T-cell-mediated autoimmune inflammatory skin disease. of superantigen produces an activating signal that induces During the course of this trial, forty-three patients received T-cell activation and proliferation( Figure 10-16) four doses of CTLA-4Ig, and 46% of this group experienced Exogenous superantigens are soluble proteins secreted by a 50% or greater sustained improvement in their skin condi- bacteria. Among them are a variety of exotoxins secreted by tion. Further studies of the utility of CTLA-4lg are also being gram-positive bacteria, such as staphylococcal enterotoxins pursued in other areas toxic-shock-syndrome toxin, and exfoliative-dermatitis Each of these binds Clonal Anergy Ensues If a Co-Stimulatory lar VB sequences in T-cell receptors(Table 10-3)and ignal ls Absent crosslinks the tcr to a class li mhc molecule Endogenous superantigens are cell-membrane proteins TH-cell recognition of an antigenic peptide-MHC complex encoded by certain viruses that infect mammalian cells. One sometimes results in a state of nonresponsiveness called group, encoded by mouse mammary tumor virus(MTv) clonal anergy, marked by the inability of cells to proliferate can integrate into the DNA of certain inbred mouse strains in response to a peptide-MHC complex. Whether clonal ex- after integration, retroviral proteins are expressed on the pansion or clonal anergy ensues is determined by the pres- membrane of the infected cells. These viral proteins, called ence or absence of a co-stimulatory signal(signal 2), such as minor lymphocyte stimulating(Mls) determinants, bind that produced by interaction of CD28 on TH cells with B7 on particular VB sequences in T-cell receptors and crosslink the antigen-presenting cells. Experiments with cultured TCR to a class II MHC molecule. Four Mls superantigens al(signal 1)in the absence of a suitable co-stimulatonp ig- originating show that, if a resting TH cell receives the TCR-mediated originating in different MTV strains, have been identified Because superantigens bind outside of the TCR antigen nal, then the TH cell will become anergic. Specifically, if binding cleft, any T cell expressing a particular Ve sequent resting TH cells are incubated with glutaraldehyde-fixed will be activated by a corresponding superantigen. Hence, APCs, which do not express B7(Figure 10-15a), the fixed the activation is polyclonal and can affect a significant per APCs are able to present peptides together with class II MHc centage(5% is not unusual) of the total TH population. The molecules, thereby providing signal 1, but they are unable to massive activations that follow crosslinkage by a superant provide the necessary co-stimulatory signal 2. In the absence gen results in overproduction of TH-cell cytokines, leading of a co-stimulatory signal, there is minimal production of cy- to systemic toxicity. The food poisoning induced by staphyallows it to bind to B7. A promising clinical trial of CTLA-4 has been conducted in patients with psoriasis vulgaris, a T-cell–mediated autoimmune inflammatory skin disease. During the course of this trial, forty-three patients received four doses of CTLA-4Ig, and 46% of this group experienced a 50% or greater sustained improvement in their skin condi￾tion. Further studies of the utility of CTLA-4Ig are also being pursued in other areas. Clonal Anergy Ensues If a Co-Stimulatory Signal Is Absent TH-cell recognition of an antigenic peptide–MHC complex sometimes results in a state of nonresponsiveness called clonal anergy, marked by the inability of cells to proliferate in response to a peptide-MHC complex. Whether clonal ex￾pansion or clonal anergy ensues is determined by the pres￾ence or absence of a co-stimulatory signal (signal 2), such as that produced by interaction of CD28 on TH cells with B7 on antigen-presenting cells. Experiments with cultured cells show that, if a resting TH cell receives the TCR-mediated sig￾nal (signal 1) in the absence of a suitable co-stimulatory sig￾nal, then the TH cell will become anergic. Specifically, if resting TH cells are incubated with glutaraldehyde-fixed APCs, which do not express B7 (Figure 10-15a), the fixed APCs are able to present peptides together with class II MHC molecules, thereby providing signal 1, but they are unable to provide the necessary co-stimulatory signal 2. In the absence of a co-stimulatory signal, there is minimal production of cy￾T-Cell Maturation, Activation, and Differentiation CHAPTER 10 235 FIGURE 10-14 CTLA-4Ig, a chimeric suppressor of co-stimulation. (a) CTLA-4Ig, a genetically engineered molecule in which the Fc por￾tion of human IgG is joined to the B7-binding domain of CTLA-4. (b) CTLA-4Ig blocks costimulation by binding to B7 on antigen pre￾senting cells and preventing the binding of CD28, a major co-stimula￾tory molecule of T cells. (a) CTLA-4Ig (b) B7 blockade by CTLA-4Ig CTLA-4 binding domain S S IgG Fc CD4 B7 CD28 T cell APC TCR tokines, especially of IL-2. Anergy can also be induced by in￾cubating TH cells with normal APCs in the presence of the Fab portion of anti-CD28, which blocks the interaction of CD28 with B7 (Figure 10-15b). Two different control experiments demonstrate that fixed APCs bearing appropriate peptide-MHC complexes can de￾liver an effective signal mediated by T-cell receptors. In one experiment, T cells are incubated both with fixed APCs bear￾ing peptide-MHC complexes recognized by the TCR of the T cells and with normal APCs, which express B7 (Figure 10-15d). The fixed APCs engage the TCRs of the T cells, and the B7 molecules on the surface of the normal APCs cross￾link the CD28 of the T cell. These T cells thus receive both signals and undergo activation. The addition of bivalent anti-CD28 to mixtures of fixed APCs and T cells also pro￾vides effective co-stimulation by crosslinking CD28 (Figure 10-15e). Well-controlled systems for studying anergy in vitro have stimulated considerable interest in this phenome￾non. However, more work is needed to develop good animal systems for establishing anergy and studying its role in vivo. Superantigens Induce T-Cell Activation by Binding the TCR and MHC II Simultaneously Superantigens are viral or bacterial proteins that bind simul￾taneously to the V domain of a T-cell receptor and to the  chain of a class II MHC molecule. Both exogenous and en￾dogenous superantigens have been identified. Crosslinkage of a T-cell receptor and class II MHC molecule by either type of superantigen produces an activating signal that induces T-cell activation and proliferation (Figure 10-16). Exogenous superantigens are soluble proteins secreted by bacteria. Among them are a variety of exotoxins secreted by gram-positive bacteria, such as staphylococcal enterotoxins, toxic-shock-syndrome toxin, and exfoliative-dermatitis toxin. Each of these exogenous superantigens binds particu￾lar V sequences in T-cell receptors (Table 10-3) and crosslinks the TCR to a class II MHC molecule. Endogenous superantigens are cell-membrane proteins encoded by certain viruses that infect mammalian cells. One group, encoded by mouse mammary tumor virus (MTV), can integrate into the DNA of certain inbred mouse strains; after integration, retroviral proteins are expressed on the membrane of the infected cells. These viral proteins, called minor lymphocyte stimulating (Mls) determinants, bind particular V sequences in T-cell receptors and crosslink the TCR to a class II MHC molecule. Four Mls superantigens, originating in different MTV strains, have been identified. Because superantigens bind outside of the TCR antigen￾binding cleft, any T cell expressing a particular V sequence will be activated by a corresponding superantigen. Hence, the activation is polyclonal and can affect a significant per￾centage (5% is not unusual) of the total TH population. The massive activations that follow crosslinkage by a superanti￾gen results in overproduction of TH-cell cytokines, leading to systemic toxicity. The food poisoning induced by staphy- 8536d_ch10_221-247 8/28/02 3:58 PM Page 235 mac76 mac76:385_reb: