Cellular mechanisms of lymphocyte-mediated lysis of tumor cells

Both branches, humoral and cellular, of the immune response have specialized mechanisms to lyse tumor cells, virus-infected cells and other targets. The effector components of the humoral response are antibodies and complement, while cytotoxic T lymphocytes (CTL) and natural killer (NK) cells are among the potent effector agents of the cell-mediated immune response. The past few years have witnessed remarkable progress in defining the effector molecules and mechanisms involved in lymphocyte-mediated killing. The recognition of target cells by CTL is antigen specific and restricted through the major histocompatibility complex (MHC). The molecular structure involved in the recognition function is the T cell receptor (TCR), associated with CD3 polypeptides. Conversely, the activity of NK cells in non antigen specific and non MHC restricted. Several surface molecules of cytotoxic lymphocytes have been identified as adhesion-mediating structures. A particular role seems to be played by a family of molecules named lymphocyte function-associated antigens (LFA) and by CD2, CD4 and CD8 antigens. Once the binding between effector and target cell has occurred, a cascade of events can be triggered leading the killer lymphocyte to deliver the lethal hit against the target cell. At least two categories of cytolytic molecules are produced by CTL and NK cells. Perforin is a protein stored in the cytoplasmic granules which forms pores in the plasma membrane of target cell leading to osmotic lysis. The other category of cytolytic factors is the group of soluble mediators which includes lymphotoxin (LT), tumor necrosis factor (TNF) and NK cytotoxic factor (NKCF). Their exact mechanism of action is presently unclear. Several cellular components are involved in the cytolytic mechanism. In particular, the cytoplasmic granules which, upon activation, release a number of cytotoxic factors by directed exocytosis and the cytoskeletal components which, modifying their organization, participate in the binding and killing processes. A growing body of evidence has recently supplied proof that target cells may play an active role in their own lysis supporting the challenging opinion of an induced suicide mechanism.