Detection of self-reactive CD8+ T cells with an anergic phenotype in healthy individuals
Finding may lead to novel therapeutic methods
A group of researchers at the Immunology Frontier Research Center , Osaka University, have clarified that CD4-positive regulatory T cells induced stable immunological unresponsiveness (anergy) in self-reactive CD8-positive T cells thereby making it possible to avoid an autoimmune response (autoimmune disorder).
Staff at IFReC associated with this project:
• Dr. MAEDA Yuka
• NISHIKAWA Hiroyoshi (Specially Appointed Associate Professor)
• SAKAGUCHI Shimon (Professor)
This group also clarified a characteristic phenotype of anergy cells and found that anergic self-reactive CD8-positive T cells in the human body suppressed autoimmune response. Although the immune system reacts to foreign antigen such as viruses, it does not normally react with an immune response to itself. (Immunological tolerance to self)
The immune system includes mechanisms of central tolerance and peripheral tolerance -- T cells responding to the self are eliminated in the thymus (central tolerance) and anergy of self-antigen is induced in the periphery (peripheral tolerance). Naturally occurring regulatory T cells prevent autoimmune response (autoimmune disorder) from happening by suppressing activation of self-active T cells; however, how regulatory T cells stably suppress self-reactive T cells for a long time and the characteristics of these suppressed cells in vivo have not been clarified.
By making use of human specimens, this group found that regulatory T cells rendered self-reactive CD8-positive T cells anergic to antigenic stimulus and induced a characteristic phenotype, clarifying the importance of the role of regulatory T cell in peripheral tolerance.
A breakdown of anergy in self-reactive CD8-positive T cells leads to the development of an autoimmune disorder. However, in the case of cancer immunity, in order to gain an effective immune response to cancer, the immune system needs to overcome anergy for the cancer antigen and produce a strong immunological response. Therefore, an understanding of anergy is important in controlling different immune responses.
The importance of anergy has been recognized over the years: however, as a phenotype of T cells, it has not been fully understood. It was thought to be difficult to use anergy for treatment. This group's achievements have demonstrated that regulatory T cells induced anergy in self-reactive CD8-positive T cells makes long-standing immune tolerance possible. Actually, in autoimmune disorder, anergy in self-reactive CD8-positive T cells is not functioning correctly.
Rendering self-reactive CD8-positive T cell anergic by making use of regulatory T cells will lead to the development of new therapeutic methods for autoimmune disorders. Methods for overcoming the anergic state will be used for a wide range of immune therapies including cancer immunotherapy.
Immunological tolerance to self requires naturally occurring regulatory T (T reg ) cells. Yet how they stably control autoimmune T cells remains obscure. Here, we show that T reg cells can render self-reactive human CD8 + T cells anergic (i.e., hypoproliferative and cytokine hypoproducing upon antigen restimulation) in vitro, likely by controlling the costimulatory function of antigen-presenting cells. Anergic T cells were naïve in phenotype, lower than activated T cells in T cell receptor affinity for cognate antigen, and expressed several coinhibitory molecules, including cytotoxic T lymphocyte–associated antigen-4 (CTLA-4). Using these criteria, we detected in healthy individuals anergic T cells reactive with a skin antigen targeted in the autoimmune disease vitiligo. Collectively, our results suggest that T reg cell–mediated induction of anergy in autoimmune T cells is important for maintaining self-tolerance.
Tregs render self-reactive human CD8+ T cells anergic
Natural cells render low-affinity self-reactive CD8+ T cells anergic upon antigen stimulation. Melan-A–specific CD8+ T cell induction. CFSE-labeled CD8+ T cells of HLA-A*0201+ healthy individuals were stimulated by Tcell–depleted, g-irradiated, and Melan-A26-35 peptide–pulsed APCs with graded numbers of CD25highCD4+ cells for 10 days. Dotted lines mean Tet–CD8+ cells showing no CFSE dilution. Control tet: NY-ESO-1157-165/HLA-A*0201 tetramer.
Detection of low-affinity anergic self-reactive CTLA-4+CCR7+CD8+ T cells in healthy individuals.
CCR7 and CD45RA expression by Tet+CD8+ T cells in an HD and a vitiligo patient. Tet, TCR-, and CD8 staining intensity of Tet+CD8+ T cells in an HD and a vitiligo patient.
To learn more about this research, please view the full research report entitled " Detection of self-reactive CD8+ T cells with an anergic phenotype in healthy individuals " at this page of the Science website.