Antigen-Specific and Antigen-Nonspecific Cellular Cytotoxicity

Sitkovsky, M

Abstract

The antigen-specific cytotoxicity mediated by cytolytic T-lymphocytes (CTL) is an important part of cellular mechanisms of anti-viral and of anti-tumor immune responses. Functions of CTL depend on their activation after the recognition of target cells which express peptide antigen in their major histocompat-ibility complex (MHC) molecules and on the susceptibility of target cells to the """"""""lethal hit""""""""- induced programmed cell death (apoptosis). Studies of CTL functions and development are now in a most interesting phase due to the latest breakthroughs in the development of different gene """"""""knock-out"""""""" mice. These studies offer the best hope to define the cells that most responsible for destruction of tumors or of virus-infected cells. Using mice with genetically disrupted beta2-microglobulin loci (beta2m-/- mice) and with a deficiency in MHC class I expression, we unexpectedly found in contrast to published reports that intraperitoneal immunization with tumor cells results in the accumulation of highly lytic and MHC class I-specific CD8+ CTL. These studies helped to demonstrate that CD8+ CTL develop even under conditions of very low level MHC class I expression, but impairment of negative and positive selection results in the generation of CTL with an unusually self-reactive recognition repertoire. Additional insights into T-cell development are being gained from studies of p53 gene (tumor suppressor gene) knock-out mice. We took advantage of the high incidence of lymphomas in these mice and established immortalized thymocyte cell lines (more than 100 different clones representing thymocytes at different stages of differentiation) for detailed studies of T-cell development. One of the spin-offs of the studies of the mechanisms of CTL-induced cell death is the promising strategy we have developed to achieve immunospecific tumor cell destruction using low concentrations of chemotherapeutic agents.