CD8+ T cell tolerance and cancer immunotherapy.
To provide protection against all foreign pathogens one can possibly encounter during their lifetime, the T cell repertoire has to be as diverse as possible. At the same time, it is desirable that the T cell repertoire remains unresponsive towards healthy tissues. To realize this self/nonself discriminatory property, T cells undergo tightly controlled selection processes during maturation in the thymus. The key parameter determining the outcome of these selection processes is the avidity of the T cells for self-MHC/self-peptide complexes expressed in the thymus; low avidity interactions result in positive selection, whereas high avidity interactions lead to negative selection. Despite the selection processes, self-tolerance is far from absolute. In many cases, this is due to the presence of self-antigen in the thymus at a level that is too low to induce thymic deletion. In addition, T cells with a low avidity for ubiquitously expressed self-antigens can escape clonal deletion and enter the periphery. A thorough understanding of the self-specific T cell repertoire is important because many potential targets for cancer immunotherapy are self-proteins. In this review, the authors discuss the impact of self-antigen expression on the CD8+ T cell repertoire. An overview of the fate and functional capacities of self-specific T cells with specificity for tissue-restricted self-antigens and for ubiquitously expressed self-antigens is provided. Furthermore, the authors discuss the influence of negative selection on the antitumor reactivity of the mature T cell repertoire.
De Visser
Karin E
KE
Department of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Schumacher
Ton N M
TN
Kruisbeek
Ada M
AM
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000502:physiology*; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000502:physiology; D007167:Immunotherapy / Q000379:methods*; D008297:Male; D051379:Mice; D018448:Models, Immunological; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D012680:Sensitivity and Specificity; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology