Cell-Mediated Effector Responses CHAPTER 14 325 peptides associated with class I MHC molecules. LFA-1 per sists in the high-avidity state for only 5-10 min after antigen tion of the CTL from the target celi rns to the low-avidity mediated activation and then it ret state. This downshift in LFA-1 avidity may facilitate dissocia- ectron microscopy of cultured Ctl clones reveals the presence of intracellular electron-dense storage granules. These granules have been isolated by fractionation and shown to mediate target-cell damage by themselves. Analysis of their contents revealed 65-kDa monomers of a pore-forming pro- tein called perforin and several serine proteases called gran zymes(or fragmentis). CTL-Ps lack cytoplasmic granules FIGURE 14-5 Scanning electron micrograph of tumor-cell attack and perforin; upon activation, cytoplasmic granules appear, by a ctl. the Ctl makes contact with a smaller tumor cell. From bearing newly expressed perforin monomers. J.D. E. Young and Z. A Cohn, 1988, Sci. Am. 258(1): 38.1 Immediately after formation of a CTL-target cell conju gate, the Golgi stacks and storage granules reorient within the cytoplasm of the Ctl to concentrate near the junction with the target cell(Figure 14-8). Evidence suggests that perforin receptor LFA-1 on the CTl membrane binds to ICAMs on monomers and the granzyme proteases are then released from the target-cell membrane, resulting in the formation of a the granules by exocytosis into the junctional space between conjugate. Antigen-mediated CTl activation converts LFA-1 the two cells. As the perforin monomers contact the target-cell from a low-avidity state to a high-avidity state(Figure 14-7). membrane they undergo a conformational change, exposing Because of this phenomenon, CTLs adhere to and form conju- an amphipathic domain that inserts into the target-cell mem- gates only with appropriate target cells that display antigenic brane; the monomers then polymerize(in the presence of Granule conjugate cytoplasmic rearrangement Target cell Ctl granule exocytosis 一( FIGURE 14-6 Stages in CTL-mediated killing of target cells. T-cell reorient towards the point of contact with the target cell, and the receptors on a CTL interact with processed antigen-class I MHc granule,'s contents are released by exocytosis. After dissociation of complexes on an appropriate target cell, leading to formation of a the conjugate, the CTL is recycled and the target cell dies by apopto. TL/target-cell conjugate. The Golgi stacks and granules in the CTL sis. /Adapted from P. A. Henkart, 1985, Annu. Rev. Immunol. 3: 31.receptor LFA-1 on the CTL membrane binds to ICAMs on the target-cell membrane, resulting in the formation of a conjugate. Antigen-mediated CTL activation converts LFA-1 from a low-avidity state to a high-avidity state (Figure 14-7). Because of this phenomenon, CTLs adhere to and form conju￾gates only with appropriate target cells that display antigenic peptides associated with class I MHC molecules. LFA-1 per￾sists in the high-avidity state for only 5–10 min after antigen￾mediated activation, and then it returns to the low-avidity state. This downshift in LFA-1 avidity may facilitate dissocia￾tion of the CTL from the target cell. Electron microscopy of cultured CTL clones reveals the presence of intracellular electron-dense storage granules. These granules have been isolated by fractionation and shown to mediate target-cell damage by themselves. Analysis of their contents revealed 65-kDa monomers of a pore-forming pro￾tein called perforin and several serine proteases called gran￾zymes (or fragmentins). CTL-Ps lack cytoplasmic granules and perforin; upon activation, cytoplasmic granules appear, bearing newly expressed perforin monomers. Immediately after formation of a CTL–target cell conju￾gate, the Golgi stacks and storage granules reorient within the cytoplasm of the CTL to concentrate near the junction with the target cell (Figure 14-8). Evidence suggests that perforin monomers and the granzyme proteases are then released from the granules by exocytosis into the junctional space between the two cells. As the perforin monomers contact the target-cell membrane, they undergo a conformational change, exposing an amphipathic domain that inserts into the target-cell mem￾brane; the monomers then polymerize (in the presence of Cell-Mediated Effector Responses CHAPTER 14 325 FIGURE 14-5 Scanning electron micrograph of tumor-cell attack by a CTL. The CTL makes contact with a smaller tumor cell. [From J. D. E . Young and Z. A. Cohn, 1988, Sci. Am. 258(1):38.] CTL CTL granule exocytosis Target cell Conjugate formation CTL-target cell conjugate CTL cytoplasmic rearrangement CTL recycling Dissociation Granule FIGURE 14-6 Stages in CTL-mediated killing of target cells. T-cell receptors on a CTL interact with processed antigen-class I MHC complexes on an appropriate target cell, leading to formation of a CTL/target-cell conjugate. The Golgi stacks and granules in the CTL reorient towards the point of contact with the target cell, and the granule’s contents are released by exocytosis. After dissociation of the conjugate, the CTL is recycled and the target cell dies by apopto￾sis. [Adapted from P. A. Henkart, 1985, Annu. Rev. Immunol. 3:31.]