Podack E R, Lowrey D M, Lichtenheld M, Hameed A
New York Medical College, Valhalla 10595.
Ann N Y Acad Sci. 1988;532:292-302. doi: 10.1111/j.1749-6632.1988.tb36347.x.
Cognate T cell-mediated functions require antigen and MHC-restricted recognition of target cells. T-effector functions comprise the delivery of signals for help, for suppression, or for cell death of the target cell. In the case of the delivery of cytotoxicity and of help for B-cell antibody production, it is known that the secretory apparatus of the effector cell participates. Prior to secretion, many components of the effector cell are stored in cytoplasmic granules. Among the important and apparently constant constituents of granules are pore-forming proteins (perforins) and proteinases (granzymes). The putative role of perforin has been thought to mediate direct cytotoxicity. It is postulated here that, in addition, perforin at low concentrations may induce target-cell endocytosis through the formation of Ca channels. Localized endocytosis of the target at the contact site in turn may lead to the uptake of locally secreted effector-cell factors, such as cytotoxic factors (CTL), lymphokines (helper cells), or suppressor factors (suppressor cells). The potential importance of such a mechanism is the delivery and uptake of secreted effector-cell components into the endosomes of target cells, bypassing the need for appropriate target-cell receptors. Perforin thus may subserve two functions depending on its intragranular concentration: one, as a killer molecule, and two, as a delivery system for additional granule factors. One of the roles of esterases in T cell-mediated cognate-effector functions may be to allow recycling of the effector cell. This apparently is achieved by an active process of detachment of the effector T cell from the target cell, possibly by way of the proteolytic cleavage of adhesion molecules. Esterases are secreted, together with perforin and other factors, during granule release at the effector target-contact site, where they can cleave intercellular adhesion molecules and thus allow effector-cell recycling and attachment to new target cells. Other roles of esterases, not discussed here, may include participation directly in the cytotoxic process through uptake into the target cell. The evidence for a common intercellular molecular delivery mechanism of cognate effector T-cell function involving perforin and esterases is summarized. This concept represents a unifying hypothesis for MHC-restricted, contact-requiring, intercellular T cell-signal delivery as well as for the delivery of cytotoxicity by non-MHC-restricted T cells and natural killer cells.
同源T细胞介导的功能需要抗原以及对靶细胞的MHC限制性识别。T效应功能包括为靶细胞提供帮助、抑制或导致其死亡的信号传递。在细胞毒性传递以及对B细胞抗体产生提供帮助的情况下，已知效应细胞的分泌装置会参与其中。在分泌之前，效应细胞的许多成分都储存在细胞质颗粒中。颗粒中重要且明显恒定的成分包括成孔蛋白（穿孔素）和蛋白酶（颗粒酶）。穿孔素的假定作用被认为是介导直接细胞毒性。本文推测，此外，低浓度的穿孔素可能通过形成钙通道诱导靶细胞内吞作用。靶细胞在接触部位的局部内吞作用反过来可能导致局部分泌的效应细胞因子的摄取，如细胞毒性因子（细胞毒性T淋巴细胞）、淋巴因子（辅助细胞）或抑制因子（抑制细胞）。这种机制的潜在重要性在于将分泌的效应细胞成分传递并摄取到靶细胞的内体中，而无需合适的靶细胞受体。因此，穿孔素可能根据其颗粒内浓度发挥两种功能：其一，作为杀伤分子；其二，作为额外颗粒因子的传递系统。酯酶在T细胞介导的同源效应功能中的作用之一可能是使效应细胞得以循环利用。这显然是通过效应T细胞从靶细胞上主动脱离的过程实现的，可能是通过粘附分子的蛋白水解切割。酯酶在效应细胞与靶细胞接触部位颗粒释放时与穿孔素及其他因子一起分泌，在那里它们可以切割细胞间粘附分子，从而使效应细胞得以循环利用并附着到新的靶细胞上。酯酶的其他作用（本文未讨论）可能包括通过摄取进入靶细胞直接参与细胞毒性过程。总结了同源效应T细胞功能涉及穿孔素和酯酶的常见细胞间分子传递机制的证据。这一概念代表了一个统一的假说，用于解释MHC限制性、需要接触的细胞间T细胞信号传递，以及非MHC限制性T细胞和自然杀伤细胞的细胞毒性传递。
