Die and Let Live: Eliminating Dangerous Lymphocytes

Abul K. Abbas Immune Privilege: Preventing Immunological Immunology Research Division Injury to Vital Organs Department of Pathology The central nervous system (CNS), testes, and eyes are Brigham and Women’s Hospital said to be immunologically privileged sites because alloand Harvard Medical School geneic or xenogeneic tissues transplanted into these Boston, Massachusetts 02115 sites are not rejected; that is, these sites are “protected” from local immune responses. It has been suggested that any injurious side effects of immunologic reactions in these tissues would have particularly devastating conThe principal physiologic function of the immune system sequences for the individual or the species. The mechais the elimination of infectious organisms. The effector nism responsible for immune privilege in the CNS, tesmechanisms that are responsible for protective immutes, and eye has interested immunologists for many nity are also capable of injuring host tissues. In some years. Much of the earlier work emphasized anatomic situations, specific immune responses have little or no factors, such as the absence of efferent lymphatics from protective value, and the harmful consequences bethe brain and the presence of vascular barriers that may come dominant; examples include autoimmune disnot allow circulating lymphocytes ready access to these eases caused by pathologic immune responses against sites. However, it has become increasingly clear that self-antigens, and infections in which the host response circulating cells can enter the eyes and testes and that and not the infectious agent is the main cause of patholantigens introduced in these sites freely enter the circuogy. The immune system has evolved multiple, nonoverlation. How, then, do these tissues maintain their privilapping mechanisms for controlling potentially harmful leged status? The surprising answer is that the testes reactions. Failure of these mechanisms may lead to tisand eyes kill any lymphocytes that come too close and sue injury and disease. Conversely, the same regulatory are activated by antigens, and this killing involves the mechanisms may be exploited therapeutically, for inFas–FasL pathway. stance, to prevent the rejection of tissue transplants. Fas is expressed on a wide variety of cell types, either Potentially injurious immune reactions may be preconstitutively (as in the liver) or inducibly, after activation vented either by functionally inactivating the responding (as in lymphocytes). FasL, on the other hand, has an lymphocytes or by killing the cells. The principal cytolytic extremely restricted tissue distribution. It is rapidly inmechanism involved in controlling lymphocyte reduced on T lymphocytes following their activation by sponses is a tightly regulated pathway of apoptotic cell antigen, but few cells other than T lymphocytes appear death triggered by an interaction of Fas (CD95) with its to express significant levels of FasL. The earliest deligand. Fas is a member of the tumor necrosis factor scription of the cloning of FasL included data showing (TNF) receptor family of cell surface proteins, and Fas that transcripts were present in the testis (Suda et al., ligand (FasL) is a member of the TNF family of membrane 1993). Based on this,Bellgrau et al. (1995) askedwhether and secreted proteins. The biochemistry of these proFasL expression in the testis was of functional importeins and the mechanisms by which Fas triggers tance. They found that testicular grafts taken from norapoptosis have been subjects of recent reviews (Nagata, mal mice and placed under the kidney capsules of allo1994; Cleveland and Ihle, 1995). This minireview focuses geneic recipients were not rejected, but if the testis on the physiological functions of the Fas–FasL pathway grafts were obtained from FasL-mutant gld/gld homozyand emphasizes the concept that, among all biological gote mice, they were rejected rapidly.This simple expersystems, only the immune system has evolved ways of iment clearly implicated the Fas pathway in the resisactively eliminating its own potentially harmful cells so that the host may survive. tance of testis allografts to rejection and suggested the