The role of thymic epithelium in the establishment of transplantation tolerance.
From experimental observations on induction of transplantation tolerance, we discuss a model that accounts for tissue-specific tolerance to antigens not expressed inside the thymus. It is postulated that antigens presented to differentiating T cells by thymic epithelium (or at large within the thymic environment) positively select and activate self-reactive T cells. A developmental program and/or prevalent conditions in the thymic environment restrict the proliferative potential and the class of effector functions that can be exerted by differentiating T cells activated in the thymus. These do not mediate inflammatory or cytolytic activities, but instead will produce the appropriate mediators to inhibit aggressive effector activities by other T cells activated in their proximity. Such "regulatory" functions will be locally expressed at the periphery upon recognition of tissue antigens shared with the thymus, towards newly formed thymic emigrants directed at tissue-specific antigens expressed by the same "target" cells. This mechanism imposes "dominant tolerance", based on specific self-recognition and predominantly established in the embryonic and neonatal period. Throughout life, the process of thymic positive selection results in all newly-formed T cells being susceptible to such suppressive mechanisms, but becoming increasingly refractory with time in the resting, post-differentiative stage. Absence of antigen (nonself) in the embryonic and neonatal life therefore allows for the accumulation of such "suppression-resistant" antigen-reactive T cells that will mount aggressive responses upon antigenic exposure. Tolerance or immunity thus represent two classes of specific immune responses, the relative predominance of which is determined by the frequency of each type of effector T cell, representing the antigenic overlap between thymic and peripheral tissues, as well as the frequency of tissue-specific T-cell generation, and the kinetics of peripheral antigenic exposure. Tolerance induced by hemopoietic cells to all other tissues is also "dominant" and based on thymic colonization and persistence of antigenic cells, with the consequent positive selection of regulatory T cells and peripheral conditions for the establishment of suppression. Upon this simple model, that ensures "interclonal class regulation" by "bridging" regulatory and effector T cells through the recognition of different antigens on the same target cell, other mechanisms which are based on V-region interactions among T cells (Ben-Nun et al. 1981, Pereira et al. 1989, Webb & Sprent 1990, Gaur et al. 1993) might well operate to ensure "dominant tolerance" by self-reactivity and class regulation.(ABSTRACT TRUNCATED AT 400 WORDS)
Coutinho
A
A
Unité d'Immunobiologie, CNRS URA 359, Institut Pasteur, Paris, France.
Salaün
J
J
Corbel
C
C
Bandeira
A
A
Le Douarin
N
N
D000818:Animals; D004848:Epithelium / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000276:immunology; D007108:Immune Tolerance; D007109:Immunity; D013950:Thymus Gland / Q000276:immunology*; D014181:Transplantation Immunology