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Shifting Paradigms in Peripheral Tolerance
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Jonathan D. Powell, Ronald H. Schwartz
What happens to a self-reactive T cell when it encounters a peripheral self antigen in the absence of costimulation? Initial studies on T cell clones had suggested that the cells do not proliferate or differentiate toward new cytokine production.15 Clones, however, are essentially memory cell populations and the rules turn out to be different for naive T cells. Insight into this question came largely from TCR transgenic mice and mice engineered to transgenically express, under tissue-specific promoters, the antigen that the T cells recognize.16-22 Typically, when naive transgenic T cells are transferred into an antigen-expressing host, the cells are activated and proliferate. In general, CD8+ T cells expand more than CD4+ T cells. In some models, the cells also differentiate to gain the ability to make IFN-γ; but in most cases the cells begin to die by 4 days. This Activation-Induced Cell Death (AICD)23 is one mechanism employed by the immune system to promote peripheral tolerance.24-27 For the most part, this death process is Fas-Fas Ligand (FasL)-dependent, although TNF has also been implicated (refer to Chapter 17).23,28,29 Presumably, signal 1 leads to the upregulation of FasL which is cleaved, solubilized and then interacts with Fas on other cells to induce death. In the presence of costimulation, this process is in part prevented by the upregulation of anti-apoptotic molecules such as Bcl-2 and Bcl-xL.30 For completeness, it should be noted that AICD can also occur in the presence of costimulation. Such death, however, is induced by reactivation of activated (memory) T cells that have entered the S phase of the cell cycle (a process known as propriocidal death).31 Whereas one might think of these mechanisms as primarily immunoregulatory, they play a key role in the tolerance process. Mice (lpr or gld) and humans (Autoimmune lymphoproliferative syndrome (ALPS) patients), possessing genetic inactivation of their Fas/FasL pathway, develop autoimmune disease.32,33
Modelling the dynamics of virus infection and immune response in space and time
Published in International Journal of Parallel, Emergent and Distributed Systems, 2019
G. Bocharov, A. Meyerhans, N. Bessonov, S. Trofimchuk, V. Volpert
The biological scheme of the model is presented in Figure 1. In the model we consider multiple non-linear feedback regulations of the population dynamics of virus infection and the antiviral immune responses. According to this general scheme, the viruses and immune cells compete for resources. The outcome of the competition results from the race between the virus infection spread on one side and the clonal CTL expansion followed by migration to the site of infection to eliminate the virus sources. Depending on the viral load and growth kinetics, the efficacy of the CTL response is determined by a balance of proliferation, anergy induction and activation-induced cell death by apoptosis. The later two take into account the tuning of lymphocytes [14], a key feature of the immune system.