The Anatomy of T-Cell Activation and Tolerance Anna Mondino*T, Alexander Khoruts*, and Marc K
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Proc. Natl. Acad. Sci. USA Vol. 93, pp. 2245-2252, March 1996 Review The anatomy of T-cell activation and tolerance Anna Mondino*t, Alexander Khoruts*, and Marc K. Jenkins Department of Microbiology and the Center for Immunology, University of Minnesota Medical School, 420 Delaware Street S.E, Minneapolis, MN 55455 ABSTRACT The mammalian im- In recent years, it has become clear that TCR is specific for a self peptide-class I mune system must specifically recognize a full understanding of immune tolerance MHC complex) T cell that will exit the and eliminate foreign invaders but refrain cannot be achieved with reductionist in thymus and seed the secondary lymphoid from damaging the host. This task is vitro approaches that separate the individ- tissues (3, 4). In contrast, cortical CD4+ accomplished in part by the production of ual lymphocyte from its in vivo environ- CD8+ thymocytes that express TCRs that a large number of T lymphocytes, each ment. The in vivo immune response is a have no avidity for self peptide-MHC bearing a different antigen receptor to well-organized process that involves mul- complexes do not survive and die by an match the enormous variety of antigens tiple interactions of lymphocytes with each apoptotic mechanism. Cortical epithelial present in the microbial world. However, other, with bone-marrow-derived antigen- cells are essential for the process of pos- because antigen receptor diversity is gen- presenting cells (APCs), as well as with itive selection because they display the self erated by a random mechanism, the im- nonlymphoid cells and their products. The peptide-MHC complexes that are recog- mune system must tolerate the function of anatomic features that are designed to op- nized by CD4+ CD8+ thymocytes and also T lymphocytes that by chance express a timize immune tolerance toward innocuous provide essential differentiation factors self-reactive antigen receptor. Therefore, self antigens and increase the efficiency of (5). Positively selected T cells continue during early development, T cells that are recognition and elimination of pathogens their journey toward the central region of specific for antigens expressed in the thy- are the subjects of this review. the thymus by first crossing the cortico- mus are physically deleted. The popula- medullary junction and then entering the tion of T cells that leaves the thymus and Thymic Tolerance medulla. The medulla contains the prod- seeds the secondary lymphoid organs ucts of positive selection-i.e., mature contains helpful cells that are specific for The thymus is the primary lymphoid organ CD4+ CD8- or CD4- CD8+ T cells, that antigens from microbes but also poten- where immature precursors develop into exit the thymus into the blood and seed tially dangerous T cells that are specific mature T cells (1). It is also the site where the secondary lymphoid tissues, where for innocuous extrathymic self antigens. immature T cells that express self-reactive they will be available to be activated by a The outcome of an encounter by a periph- T-cell antigen receptors (TCRs) are elim- foreign peptide-MHC complex. eral T cell with these two types ofantigens inated (2). The thymus is organized into The population of positively selected is to a great extent determined by the three physically distinct areas: the outer cortical T cells will include cells that have inability of naive T cells to enter nonlym- subcapsular zone, the cortex, and the in- a strong avidity for self peptide-MHC phoid tissues or to be productively acti- ner medulla (1). The subcapsular zone is a complexes that are expressed on thymic vated in the absence of inflammation. thin space that lies directly below the outer APCs. These T cells are potentially auto- capsule that encases the thymus. This area reactive and must be eliminated. Work Current evidence indicates that self- contains the most immature CD4- CD8- from many laboratories has shown that reactive lymphocytes can be inactivated at T-cell precursors that have recently mi- this occurs via physical deletion involving all stages of their development by a variety grated to the thymus from the bone mar- apoptosis (6). Experiments with TCR of mechanisms. Perhaps the best under- row. From the subcapsular zone, the im- transgenic mice that also express the an- stood is clonal deletion of lymphocytes at mature T cells migrate deeper into the tigen the transgenic T cells are specific for an early stage of development in the pri- thymus and enter the cortex, which is have shown that clonal deletion can occur mary lymphoid organs- e.g., T cells in the richly populated by a special type of epi- either early in the CD4+ CD8+ stage in thymus-if their antigen receptors have a thelial cell that expresses high levels of the cortex (7, 8) or later in the CD4+ high affinity for self antigens expressed class I and II major histocompatibility CD8+ stage in the medulla (9, 10). The there. However, this process alone cannot complex (MHC)-encoded molecules. In site where a given self-reactive T cell will account for tolerance that exists toward the cortex, the T-cell precursors begin to be deleted in the thymus is probably de- antigens that are not well expressed in the express both CD4 and CD8 and to rear- termined by the location of the cells that primary lymphoid organs. Examples of range their TCR a and 13 genes such that present the relevant self peptide-MHC such antigens are proteins that are ex- each cell will express a different rear- complex (6). In cases where T cells are pressed exclusively in the parenchymal ranged TCR-a(3 heterodimer. The speci- deleted early in the CD4+ CD8+ stage in tissues, proteins that are only expressed at ficity of the TCR expressed by a given the cortex, the relevant complex is prob- certain developmental stages of the or- CD4+ CD8+ thymocyte for a peptide- ably presented by cortical epithelial cells. ganism, and the infinite variety of other- MHC complex expressed on another cell Because blood-borne macromolecules wise innocuous environmental proteins (the APC) will determine the thymocyte's fate. present in the air and diet. Because pep- Evidence from fetal thymic organ Abbreviations: APC, antigen-presenting cell; tides derived from these proteins are pre- cultures suggests that a CD4+ CD8+ thy- HEL, hen egg lysozyme; IL, interleukin; MHC, sented to mature T cells outside of the mocyte that expresses a TCR with low but major histocompatibility complex; PALS, peri- thymus, peripheral tolerance cannot be measurable avidity for a self peptide- arterial lymphatic sheath; TCR, T-cell antigen explained by a developmentally regulated MHC complex will be "positively select- receptor; TNF, tumor necrosis factor; TGF-f3, to as in case of that it will transforming growth factor f; HEV, high en- susceptibility deletion, the ed," is, be allowed to differen- dothelial venule. immature T cells, but rather depends on tiate into a mature CD4+ CD8- (if its *A.M. and A.K. contributed equally to the factors that are extrinsic to the self- TCR is specific for a self peptide-class II preparation of this manuscript. reactive T cell. MHC complex) or a CD4- CD8+ (if its tTo whom reprint requests should be addressed. 2245 Downloaded by guest on September 28, 2021 2246 Review: Mondino et al. Proc. Natl. Acad. Sci. USA 93 (1996) have poor access to the cortex (11), cor- blown reactivity to extrathymic self anti- their activation. The spleen has a similar tical clonal deletion is probably most rel- gens is to be prevented. organization but is unique among second- evant for antigens that are produced by ary lymphoid organs because it lacks af- the cortical epithelial cells themselves- Lymphocyte Migration Through ferent lymphatic drainage and is thus ded- e.g., MHC molecules and housekeeping Secondary Lymphoid Tissues icated to process blood-borne antigens proteins-or are produced in large exclusively. The spleen is divided into the amounts by other cells in the cortex-e.g., After T cells leave the thymus, they recir- red pulp, which contains red blood cells thymic hormones. In several cases where T culate between the blood and lymph with and macrophages, and the white pulp, cells are deleted in the medulla, the rele- intermediate stops in secondary lymphoid which has T- and B-cell-rich areas like the vant antigen is preferentially produced by tissues (13) (lymph nodes, Peyer's patches, lymph nodes (Fig. 1B). A central artery bone marrow-derived medullary APCs (9) and the spleen) (1). The secondary lym- enters the spleen and branches into arte- or is preferentially picked up from the phoid tissues are designed to co-localize rioles that end in splenic sinuses present in serum, processed, and presented by med- antigen, APCs, and naive T and B cells. the red pulp. The arterioles dump their ullary APCs (10). This process is facili- Peripheral lymph nodes are strategically contents of blood cells and fluids into the tated by the concentration of interdigitat- located throughout the body to collect and sinuses, providing the major means by ing dendritic cells, the most potent induc- process antigens arriving via the lymphatic which blood-borne material enters the ers of clonal deletion (12), at the vasculature. Lymphatic vessels originate spleen. T cells and interdigitating den- corticomedullary junction (1). as closed-end capillaries that collect tis- dritic cells are concentrated along the sue-derived lymph fluid and lymphocytes. length of the arterioles to form the peri- The Peripheral Tolerance Paradox Not surprisingly, the richest networks of arterial lymphatic sheath (PALS) that lymphatic vessels are found in sites of constitutes the T-cell-rich zone of the Because clonal deletion of self-reactive T greatest foreign antigenic load-e.g., skin spleen and is analogous to the lymph node cells in the thymus is such an efficient and mucosal surfaces (1).