Structure and Function of Perforin

Abstract

The most striking aspect of lymphocyte-mediated cytolysis is the formation of membrane lesions on target membranes as first described by Dourmashkin et al. (1980). In these early studies, a mixed population of effector cells was used, leaving open the question as to whether the observed membrane lesions were in fact assembled by cytotoxic lymphocytes. Subsequent studies by Podack and Dennert using clonal populations of cytotoxic effector lymphocytes demonstrated that the membrane lesions in fact arose from precursor molecules contained in cloned natural Killer (NK) and T cells (Dennert and Podack 1983; Podack and Dennert 1983) that were transferred to and assembled on target membranes. Similar analyses were carried out by Henkart et al. (1985) using a cytolytic rat tumor cell line of large granular morphology. These results led to the concept that some aspects of lymphocyte-mediated cytolysis are quite similar to the mechanism of complement-mediated cytolysis (for review, see Podack 1986; Podack and Tschopp 1984). Because the effector molecule of cytotoxic lymphocytes seemed to perforate the target membrane, it was designated “perforin 1” or “P1” (Dennert and Podack 1983). The assembly of P1 into transmembrane tubules resembles the formation of complement membrane lesions by polymerization of C9 (Tschopp et al. 1982; Podack and Tschopp 1982b). The membrane lesions formed by effector lymphocytes were therefore designated “poly perforin” or “poly P1.”