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FIGURE 9-5 The B7 and CD28 families. The known B7 family ligands expressed on APCs and CD28 family receptors expressed on T cells are shown, with their expression patterns and likely major functions. Other inhibitory receptors have been defined, such as BTLA, but these are not homologous to CD28 and are therefore not shown here.

FIGURE 9-5 The B7 and CD28 families. The known B7 family ligands expressed on APCs and CD28 family receptors expressed on T cells are shown, with their expression patterns and likely major functions. Other inhibitory receptors have been defined, such as BTLA, but these are not homologous to CD28 and are therefore not shown here.

The interaction of CD40L on T cells with CD40 on APCs enhances T cell responses by activating the APCs.

CD40 ligand (CD40L) is a TNF superfamily membrane protein that is expressed primarily on activated T cells, and CD40 is a member of the TNF receptor superfamily expressed on B cells, macrophages, and dendritic cells. The functions of CD40 in activating macrophages in cellmediated immunity and activating B cells in humoral immune responses are described in Chapters 10 and 11, respectively. Activated helper T cells express CD40L, which engages CD40 on the APCs and activates the APCs to make them more potent by enhancing their expression of B7 molecules and secretion of cytokines such as IL-12 that promote T cell differentiation (Fig. 9-6). This phenomenon is sometimes called licensing because activated T cells license APCs to become more powerful stimulators of immune responses. Thus, the CD40 pathway indirectly amplifies T cell responses by inducing costimulators on APCs, but CD40L does not function by itself as a costimu-lator for T cells.

Therapeutic Costimulatory Blockade

New therapeutic agents are being developed for suppression of injurious immune responses on the basis of the understanding of these costimulatory pathways (Fig. 9-7). CTLA-4-Ig, a fusion protein consisting of the extracellular domain of CTLA-4 and the Fc portion of human IgG, binds to B7-1 and B7-2 and blocks the B7:CD28 interaction. The reason for use of the extracellular domain of CTLA-4 rather than of CD28 to block B7 molecules is that CTLA-4 binds to B7 with a 20- to 50-fold greater affinity, as mentioned before. Attachment of the Fc portion of IgG increases the in vivo half-life of the protein. CTLA-4-Ig is an approved therapy for rheumatoid arthritis, and clinical trials are currently assessing its efficacy in the treatment of transplant rejection, psoriasis, and Crohn's disease. Antibodies that block the inhibitory receptors CTLA-4 and PD-1 are in clinical trials for the immunotherapy of tumors. As one might predict from the role of CTLA-4 in maintaining self-tolerance, blocking of this inhibitory receptor induces autoimmune

T cells recognize antigen (with or without B7 costimulators), causing expression of CD40L on T cells

CD40L binds to CD40 on DC; leads to DC expression of B7; secretion of cytokines

Activated DCs stimulate T cell proliferation and differentiation

Apcs And Costimulators

FIGURE 9-6 Role of CD40 in T cell activation. Naive T cells are activated by peptide-MHC complexes on activated APCs. Antigen recognition by T cells together with costimulation (not shown in the figure) induces the expression of CD40 ligand (CD40L) on the activated T cells. CD40L engages CD40 on APCs and may stimulate the expression of B7 molecules and the secretion of cytokines that activate T cells. Thus, CD40L on the T cells makes the APCs "better" APCs, and thus promotes and amplifies T cell activation.

FIGURE 9-6 Role of CD40 in T cell activation. Naive T cells are activated by peptide-MHC complexes on activated APCs. Antigen recognition by T cells together with costimulation (not shown in the figure) induces the expression of CD40 ligand (CD40L) on the activated T cells. CD40L engages CD40 on APCs and may stimulate the expression of B7 molecules and the secretion of cytokines that activate T cells. Thus, CD40L on the T cells makes the APCs "better" APCs, and thus promotes and amplifies T cell activation.

reactions in some patients. Inhibitors of the CD40L:CD40 pathway are also in clinical trials for transplant rejection and chronic inflammatory autoimmune diseases.

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