There are several characteristics of tolerance in T- and B-lymphocyte populations. It is important to appreciate the general principles before we discuss the specific mechanisms of tolerance in these lymphocytes.
The mechanisms of tolerance eliminate and inactivate lymphocytes that express high-affinity receptors for self antigens. All individuals inherit essentially the same antigen receptor gene segments, and these recombine to form functional genes that are expressed in lymphocytes as the cells arise from precursor cells. The specificities of the receptors encoded by the recombined genes are random and are not influenced by what is foreign or self for each individual. It is not surprising that during this process of generating a large and diverse repertoire, some developing T and B cells in every individual may express receptors capable of recognizing normal molecules in that individual (i.e., self antigens). Therefore, there is a risk for lymphocytes to react against that individual’s cells and tissues, causing disease. The mechanisms of immunologic tolerance prevent such reactions.
Tolerance is antigen specific, resulting from the recognition of antigens by individual clones of lymphocytes. This contrasts with therapeutic immunosuppression, which affects lymphocytes of many specificities. The key advances that allowed immunologists to study tolerance were the ability to induce this phenomenon in animals by exposure to defined antigens under various conditions and to then analyze the survival and functions of the lymphocytes that had encountered the antigens. In the 1950s, Peter Medawar and colleagues showed that neonatal mice of one strain exposed to cells from other strains became unresponsive to subsequent skin grafts from the donor strain. Later studies showed that tolerance could be induced not only to foreign cells but also to proteins and other antigens. Any antigen may be an immunogen or a tolerogen, depending on numerous factors, such as antigen exposure during lymphocyte maturation and recognition by specific lymphocytes in the presence or absence of innate immune responses.
Self-tolerance may be induced in immature self-reactive lymphocytes in the central (generative, or primary) lymphoid organs (central tolerance) or in mature lymphocytes in peripheral sites (peripheral tolerance) (Fig. 1). Central tolerance ensures that the repertoire of mature lymphocytes becomes incapable of responding to self antigens that are expressed in the generative lymphoid organs (the thymus for T cells and the bone marrow for B lymphocytes). However, central tolerance is not perfect, and many self-reactive lymphocytes complete their maturation and are present in healthy individuals. Therefore, the mechanisms of peripheral tolerance are needed to prevent activation of these potentially dangerous lymphocytes.
Fig1. Central and peripheral tolerance to self antigens. In central tolerance, immature lymphocytes specific for self antigens may encounter these antigens in the generative lymphoid organs (referred to as central organs in the context of tolerance induction) and are deleted, change their specificity (B cells only), or (in the case of CD4+ T cells) develop into regulatory lymphocytes (regulatory T cells [Tregs]). In peripheral tolerance, some self-reactive lymphocytes may mature and enter peripheral tissues and may be inactivated or deleted by an encounter with self antigens in these tissues or are suppressed by the Tregs (peripheral tolerance). APC, Antigen-presenting cell.
Central tolerance occurs during a stage in the maturation of lymphocytes when an encounter with an antigen may lead to cell death or replacement of a self-reactive antigen receptor with one that is not self-reactive. As lymphocytes are maturing in the generative lymphoid organs, immature cells may encounter antigens in these organs. The antigens that are present in these organs are mostly self antigens because foreign (e.g., microbial) antigens that enter from the external environment are typically captured and taken to secondary lymphoid organs, such as the lymph nodes, spleen, and mucosal lymphoid tis sues, and are not concentrated in the thymus or bone marrow. The antigens normally present in the thymus and bone mar row include ubiquitous, or widely disseminated, self antigens, some of which may be expressed by cells in the central organs and others may be brought in by the blood. In addition, many peripheral tissue-specific antigens are expressed in the thymus by a special mechanism that is described later. Therefore, in the central lymphoid organs, the immature lymphocytes that recognize antigens are typically cells with high-affinity receptors specific for self antigens. The fates of these immature lymphocytes are described later (see Fig. 1).
Peripheral tolerance is maintained primarily by regulatory T cells (Tregs) that actively suppress the activation of lymphocytes specific for self and other antigens. Treg-mediated suppression occurs in secondary lymphoid organs and non lymphoid tissues. In addition to suppressing immune responses to self antigens in peripheral tissues, Tregs may also prevent responses to antigens derived from commensal microbes, or from the fetus in pregnant females.
Mature lymphocytes that recognize self antigens in peripheral tissues become incapable of activation by reexposure to that antigen or die by apoptosis. These mechanisms of peripheral tolerance are important for maintaining unresponsiveness to self antigens that are expressed in peripheral tissues and not in the generative lymphoid organs.
Some self antigens are sequestered from the immune system and other antigens are ignored. Antigens may be sequestered from the immune system by anatomic barriers, such as in the testes and eyes, and thus cannot engage antigen receptors (see Chapter 14). In experimental models, some self antigens are available for recognition by lymphocytes but, for unknown rea sons, fail to elicit any response and are functionally ignored. The importance of this phenomenon of ignorance for the maintenance of self-tolerance is not established.
The induction of immunologic tolerance is a possible therapeutic strategy for preventing harmful immune responses in autoimmune and allergic diseases and transplant rejection. Tolerance induction may also be useful for preventing immune reactions to the products of newly expressed genes or viral vectors in gene therapy protocols, for preventing reactions to injected proteins in patients with deficiencies of these proteins (e.g., patients with hemophilia treated with Factor VIII), and for promoting acceptance of stem cell transplants.
Experimental approaches, especially the creation of genetically modified mice, have provided valuable models for analysis of self-tolerance, and many of our current concepts are based on studies with such models. Furthermore, by identifying mutations and genetic polymorphisms that may be associated with autoimmunity in mice and humans, it has been possible to deduce some of the mechanisms of self-tolerance. However, for most self antigens, we do not know which ones induce central or peripheral tolerance (or are ignored). More importantly, it is also not known which tolerance mechanisms fail in common human autoimmune diseases, and this remains a major challenge in understanding autoimmunity.
