【正文】 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 costimulatory molecules, and cause intracellular signaling, resulting in activation of the lymphocyte and production of cytokines. Figure 161 Lineage relationships of maturing T cells. γδTcell receptor (TCR) and αβTCR–expressing cells are separate lineages that develop from a mon precursor. In the αβ lineage, the majority of thymocytes express both CD4 and CD8. TCR expression mences in this doublepositive stage, beginning with low numbers of receptors on each cell and increasing as maturation proceeds. Singlepositive (., CD4 or CD8 αβTCR–expressing mature cells) are selected from this population. Some αβ cells express CD4 or CD8. 12 TLymphocyte Activation Tcell activation is an elegant series of events that are still in the process of full delineation ( Fig. 16–2 ). Antigen recognition by T cells is the initiating stimulus for their activation, proliferation, cytokine production, and performance of regulatory or cytolytic effector functions. The TCR is posed of membrane proteins expressed only on T lymphocytes. The TCR does not recognize soluble antigens。 rather, it must recognize antigen in the context of peptide (613 amino acids in length)/MHC plexes on the surface of APCs. Associated with the TCR is the CD3 molecule. Together they constitute the TCR plex. Figure 162 Overview of intracellular signaling events during Tcell activation. Immediately after the Tcell receptor (TCR) binds antigen on an antigenpresenting cell (APC), several protein tyrosine kinases are activated, and these enzymes phosphorylate substrates, which leads to activation of guanosine triphosphate (GTP)–binding proteins such as Ras and activation of enzymes that break down membrane phospholipids. 13 Most TCRs are heterodimers, consisting of two transmembrane polypeptide chains designated α and β, which are bonded covalently. All TCRs have a variable region that confers antigen specificity. The αβTCR is noncovalently associated with CD3. This highly conserved plex of proteins is responsible for providing the signaling ponents to the antigenbinding TCR heterodimer, which binds the antigen. Binding of a foreign antigen results in the conformational change in the plex. The associated CD3 molecules transduce the intracellular signals after antigen binding occurs. The development of monoclonal antibodies directed against CD3, such as OKT3, which interfere with Tcell function by altering or inhibiting the intracellular signaling, have played a significant clinical role in an transplantation. Both MHC molecules and αβTCR are expressed on resting T cells。 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