Hepatocyte entry leads to degradation of autoreactive CD8 T cells

Abstract

Although most self-reactive T cells are eliminated in the thymus, mechanisms to inactivate or control T cells specific for extrathymic antigens are required and exist in the periphery. By investigating the site in which autoreactive T cells are tolerized, we identify a unique mechanism of peripheral deletion in which naïve autoreactive CD8 T cells are rapidly eliminated in the liver after intrahepatic activation. T cells actively invade hepatocytes, enter endosomal/lysosomal compartments, and are degraded. Blockade of this process leads to accumulation of autoreactive CD8 T cells in the liver and breach of tolerance, with the development of autoimmune hepatitis. Cell into cell invasion, or emperipolesis, is a long-observed phenomenon for which a physiological role has not been previously demonstrated. We propose that this "suicidal emperipolesis" is a unique mechanism of autoreactive T-cell deletion, a process critical for the maintenance of tolerance.

Antigen expression level threshold tunes the fate of CD8 T cells during primary hepatic immune responses

“…Regardless of de novo (rAAV.K b treatment in this study) or transgenic [Alb-K b mice (8,13,17,25)] expression, Des T cells activated by hepatocytes never developed into CTL, a finding similarly observed for OT-I T cells activated intrahepatically by de novo-expressed loweraffinity ligands. Overall, a wide variety of outcomes have been reported after intrahepatic CD8 T-cell activation in mice expressing transgenic liver antigens, including ignorance (33), deletional tolerance (8,13,17,25), and partial or full effector differentiation (11,12,24,34). These variable outcomes are likely caused by the different TCR:pMHC affinity and/or levels of antigen expression in these models.…”

“…First, this study ends an ongoing debate over whether T-cell tolerance observed in transgenic models is primarily a result of central tolerance or other regulatory mechanisms caused by constitutive transgene expression (11,12). Regardless of de novo (rAAV.K b treatment in this study) or transgenic [Alb-K b mice (8,13,17,25)] expression, Des T cells activated by hepatocytes never developed into CTL, a finding similarly observed for OT-I T cells activated intrahepatically by de novo-expressed loweraffinity ligands. Overall, a wide variety of outcomes have been reported after intrahepatic CD8 T-cell activation in mice expressing transgenic liver antigens, including ignorance (33), deletional tolerance (8,13,17,25), and partial or full effector differentiation (11,12,24,34).…”

“…We recently described two mechanisms involved in impairing effector responses after intrahepatic activation: nonapoptotic degradation of T cells in hepatocyte lysosomes within the first day of activation ["suicidal emperipolesis" (25)] and Bimdependent apoptosis of T cells surviving suicidal emperipolesis (17). Although donor OT-I cells initially retained in the liver were efficiently deleted in mice treated with high-dose rAAV.…”

Individual Stability of Stereotypes of Immune Reacting and Modern Possibilities of Their Diagnostic in Organ Transplantation (Immune-Physiological Analysis of a Problem)

“…В случае пря-мого распознавания аллоантигенов на клетках эн-дотелия донорского органа (комплекса молекулы HLA I класса с аллоантигеным пептидом) наив-ными Т-лимфоцитами реципиента, имеющимися в циркуляции, происходит анергия и затем гибель апоптозом этих наивных Т-лимфоцитов из-за недо-статка ко-стимулирующих молекул [30,31]. Поэто-му при грамотно проведенной иммуносупрессии в организме не сохраняется стереотип клеток высо-коаффинной иммунологической памяти и после ре-генерации органа, а также элиминации АПК донора (вероятность острого отторжения как раз характе-ризует срок их жизни), процесс распознавания до-норских антигенов и формирование иммунного сте-реотипа начинается как бы заново.…”

A nonmainstream approach against cancer

“…We want to emphasize that to get to the discovery of new tumor biomarkers and/or molecular targets for new anticancer approaches, the mainstream approach is a genomic investigation, which in fact is not leading to remarkable and useful discovery for epochal changes in cancer patients' management. In fact, tumor cannibalism is included in a list of so called ''cell-in-cell phenomena'', together with entosis (overholtzer), ''emperitosis'', ''emperipolesis'' and ''suicidal emperipolesis'' [30][31][32][33][34] . An interesting debate on this issue may be read online in ''It's a Cell-Eat-Cell World'' By Jef Akst (1 August 2011, The Scientist).…”