Function of granule perforin and esterases in T cell-mediated reactions. Components required for delivery of molecules to target cells

Abstract

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.