【正文】 however, the IL2 receptor (IL2R) is expressed at only very low levels. When Tcell activation occurs, there is a decrease in the number of TCRs expressed on the T cell, acpanied by an increase in IL2R expression. Molecular signaling via the TCR/CD3 plex and its relationship with IL2 production and IL2R expression have been characterized. Antigen binding initiates the activation of two signaltransduction pathways through a conformational change in the TCR plex. The beta chain of the plex is phosphorylated by means of a CD4 or CD8associated tyrosinekinase–dependent pathway. The activated TCR plex is coupled via a Gbinding protein to 14 phospholipase C. The activation of phospholipase C results in the hydrolysis of phosphatidylinositol 4,5 biphosphate (PIP2 ) to produce diacylglycerol (DAG) and inositol 1,4,5triphosphate (IP3 ). These are the second messengers that are responsible for the mobilization of intracellular and extracellular Ca2 + that activate protein kinase C. The result of these changes is the transcription of earlyactivation genes (NFAT and cfos) and the production of messenger RNA (mRNA) for IL2 and its receptor ( Fig. 16–3 ). Figure 163 Tcell signaling through membrane inositol lipid metabolism. Tcell receptor (TCR)– associated protein tyrosine kinases activated by antigen presentation lead to the phosphorylation of phosphatidylinositol phospholipase Cγ (PIPLCγ1) as well as docking sites for PIPLCγ1 on the plasma membrane. PIPLCγ1, activated tyrosine phosphorylation, catalyzes the breakdown of membrane phosphatidylinositol 4, 5bisphosphate (PIP2 ), generating inositol 1,4,5triphosphate (IP3 ) and diacylglycerol (DAG). IP3 induces the release of Ca2 + stored in the endoplasmic reticulum (ER), and DAG plus Ca2 + activate protein 15 kinase C (PKC). Ca2 + and PKC both serve to activate other enzymes and eventually transcription factors. The symbol (P) refers to phosphorylated tyrosine. Costimulatory Pathways Two signals are required for Tcell activation: an antigenspecific signal and a costimulatory signal. The TCR/CD3 interaction (signal 1) required for cell activation has been well defined. The costimulatory pathways present on APC surface molecules provide the second signal for Tcell activation (signal 2). Costimulatory molecules on the Tcell surface specifically interact with molecules on the APC surface. The most well characterized costimulatory important pathway involves the Tcell surface molecule CD28. This molecule binds to both CD80 (B71) and CD86 (B72) found on APCs (dendritic cells, monocytes, B cells), and signaling through CD28 enhances the Tcell response to antigens ( Fig. 16–4 ). To balance enhancing response is another Tcell surface molecule that inhibits Tcell activation, CD152 (CTLA4). Closely related to this CD28/CD152/CD80/CD86 pathway is the CD40/CD154 (also known as CD40 ligand) pathway. This interaction of CD40/CD154 provides the stimulus for B cells to continue activation and proliferation.[15] Costimulatory blockade using antiCD154 monoclonal antibodies is very effective in inducing anergic and regulatory T cells. 16 Figure 164 Costimulators on antigenpresenting cells (APCs) are required for effective Tcell activation. Resting macrophage APCs do not express costimulatory molecules such as B71 (CD80) or B72 (CD86), and they fail to activate T cells during antigen presentation. In the setting of an infection, microbial products such as endotoxin or cytokines elaborated by innate immune responses can upregulate B71 (CD80) and B72 (CD86) expression on the macrophage. Antigen presentation by the activated macrophage will then lead to Tcell activation characterized by cytokine production and proliferation. Cytokines secreted by the activated T cell, such as interferonγ, can induce costimulator expression on other macrophages, enabling them to serve as effective APCs and thereby amplifying the immune response. TCell Effector Functions In addition to acquiring the TCR plex during thymic maturation, T cells also acquire differentiation receptors called cluster of differentiation (CD) antigens. CD4 and CD8 are the bestknown CD markers. Other frequently occurring CD 17 markers can be found in Table 16–2 . The subpopulations of T cells have several different functional activities. T cells bearing the CD8+ molecule interact with MHC class I/peptide plexes and can directly lyse a foreign or tumor cell on activation. These activated CD8+ T cells are the cytotoxic T lymphocytes (CTLs). In contrast, CD4+ T cells recognize antigen in the context of MHC class II molecules. CD4+ T cells bee T helper (TH ) cells after activation and primarily function through the secretion of distinct cytokines to induce either a cellmediated response (TH 1) or a humoral response (TH 2). Even the recognition of foreign cells is a plex process. The initial responding and proliferating cells do not destroy foreign grafts。 this is termed growth factor withdrawal. CELLTOCELL INTERACTIONS Once confronted with an antigen, the response of the lymphocytes is plex. Multiple celltocell interactions are required to produce the immune response. T 11 cells, B cells, APCs, and cytokines all play a role. Critical to this response are the professional APCs—dendritic cells and macrophages—that bind antigen and present it to T and B cells. Protein antigens need to be digested by phagocytic cells before the antigenic information can be presented to the lymphocyte for self and nonself recognition by MHC. In addition, activated macrophages produce and secrete IL1, a cytokine that further amplifies the response and stimulates T and Bcell activation. For a productive immune response to be generated, the TCR plex must bind to the MHC on the APC, be stabilized by co