Mature Effectors

pertofin/yanzymes

AƧ'cliiss II MHC

DMA fragmentation Coll lysis

Figure 2 Perforin/granzyme granule exocytosis and FasL/Fas cytotoxicity mediated by CD8 and CD4' CTLs.

Dubos) using nonionic detergent to dissolve the target cell membranes. The lytic activity by particular cytotoxic T cell populations can be compared with that of another population by comparing lytic units. A lytic unit (LU) is the number of effectors required to achieve an arbitrary amount of lysis (e.g. 50%) in a particular amount of time (e.g. 4 h) using data derived from a range of effector-to-target ratios. Events in cytolysis generally fall into three stages termed 1) conjugate formation or adherence, 2) lethal hit delivery, and 3) target cell lysis or disintegration. A detailed discussion of these stages can be found elsewhere (see Mechanisms of cytolysis above). Both specific and nonspecific conjugates can form between T cells and target cells in the presence of Mg2" via LFA-1 and its coreceptor ICAM-1, CD2 and its coreceptor LFA-3. For perforin/granzyme cytolysis, the lethal hit delivery is both temperature and calcium dependent. Target cell disintegration can occur in the absence of the CTL following the lethal hit. CTLs can recycle, i.e. kill more than one target cell. De novo protein synthesis is not required for perforin-mediated cytolysis as the perforin exists in preformed granules, but it is required for FasL expression. A hallmark of short-term CTL assays (4-6 h), is that there is no bystander killing of nearby nonspecific target cells. T cell-mediated cytolysis is unidirectional killing in that CTLs are spared the lethal hit delivery by some unknown mechanism.

Cytoplasmic granules in CTLs contain perforin (or cytolysin) and members of a family of serine esterases (granzymes). Secretion of granzyme A activity into the medium following cytotoxic T cell/target cell interaction has been used as an assay of granule exocytosis but not necessarily cytolysis. There is clonal variation with regard to granzyme A content and mice genetically manipulated to be granzyme A deficient retain cytolytic activity while mice rendered granzyme B deficient are deficient in cytolytic T cells.

Cytokines reported to be released following killer target cell interaction are IFNy and lymphotoxin (LT) in addition to the previously mentioned TNFot. The in vivo release and function of these cytokins are under investigation. It is unlikely that they play a direct role in short term in vitro cytolysis since there is little bystander killing and cytolytic activity is not demonstrable in supernatants of killer T cells cocul-tured with specific target cells.

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