Date Published: March 20, 2014
Publisher: Public Library of Science
Author(s): Shiki Takamura, Eiji Kajiwara, Sachiyo Tsuji-Kawahara, Tomoko Masumoto, Makoto Fujisawa, Maiko Kato, Tomomi Chikaishi, Yuri Kawasaki, Saori Kinoshita, Manami Itoi, Nobuo Sakaguchi, Masaaki Miyazawa, Michael S. Diamond.
In chronic viral infections, persistent antigen presentation causes progressive exhaustion of virus-specific CD8+ T cells. It has become clear, however, that virus-specific naïve CD8+ T cells newly generated from the thymus can be primed with persisting antigens. In the setting of low antigen density and resolved inflammation, newly primed CD8+ T cells are preferentially recruited into the functional memory pool. Thus, continual recruitment of naïve CD8+ T cells from the thymus is important for preserving the population of functional memory CD8+ T cells in chronically infected animals. Friend virus (FV) is the pathogenic murine retrovirus that establishes chronic infection in adult mice, which is bolstered by the profound exhaustion of virus-specific CD8+ T cells induced during the early phase of infection. Here we show an additional evasion strategy in which FV disseminates efficiently into the thymus, ultimately leading to clonal deletion of thymocytes that are reactive to FV antigens. Owing to the resultant lack of virus-specific recent thymic emigrants, along with the above exhaustion of antigen-experienced peripheral CD8+ T cells, mice chronically infected with FV fail to establish a functional virus-specific CD8+ T cell pool, and are highly susceptible to challenge with tumor cells expressing FV-encoded antigen. However, FV-specific naïve CD8+ T cells generated in uninfected mice can be primed and differentiate into functional memory CD8+ T cells upon their transfer into chronically infected animals. These findings indicate that virus-induced central tolerance that develops during the chronic phase of infection accelerates the accumulation of dysfunctional memory CD8+ T cells.
Antigen-specific CD8+ T cell populations are a major component that eliminate cells infected with intracellular pathogens. After infections that are cleared acutely, antigen-specific CD8+ T cells can differentiate into functionally competent memory CD8+ T cells, and can persist for a long time in the apparent absence of relevant antigens . In contrast, in the case of chronic infections where the antigens are presented persistently, CD8+ T cells primed during the early phase of infection succumb to progressive functional defects, such as impaired ability to proliferate, kill infected cells, and/or produce effector cytokines in response to the antigen-specific stimulation . In most cases, this loss of effector functions is due to signaling through inhibitory molecules such as programmed cell death 1 (PD-1), lymphocyte activation gene 3 (LAG-3), CD244, CD160, and T cell Ig domain and mucin domain 3 (Tim-3), and is called exhaustion . The severity of this dysfunction, which is in correlation with the numbers and extent of inhibitory molecules expressed on exhausted CD8+ T cells, is critically linked with the levels of repetitive exposure to the relevant antigen . In addition to their negative effects on the functionality of antigen-experienced CD8+ T cells, persisting antigens also induce stable proliferation of already-exhausted memory CD8+ T cells . The resultantly sustained numbers of functionally impaired memory CD8+ T cells potentially inhibit optimal priming of otherwise functional fresh memory CD8+ T cells via physiological competition for the niche. Thus, chronic infection is a vicious circle of ongoing CD8+ T cell dysfunction and ineffective antigen clearance. Despite such detrimental effects, however, recent studies shed light on a beneficial role of persistent antigens on the functionalities of memory CD8+ T cells. Naïve CD8+ T cells are continuously provided from the thymus even during the chronic phase of infection, and this continual thymic output can result in the priming of new antigen-specific CD8+ T cells . Unlike exhausted CD8+ T cells that were primed in the early phase of infection, CD8+ T cells primed during the chronic phase of infection in low-antigen and less intensive inflammatory settings give rise to functional memory CD8+ T cells capable of mounting authentic recall responses . Similar memory-dominated differentiation of CD8+ T cells can also be found when CD8+ T cells are primed after the peak of an acute infection, by the time that the majority of antigens have been cleared out . Thus, persistent antigens play an important role in generating functional memory CD8+ T cells in the presence of continual thymic output.
Recognition of self-antigens in the thymus is essential for the deletion of self-reactive thymocytes. In addition, silencing selection-escaped CD8+ T cells via abundant antigens and PD-1-mediated costimulation in the periphery is one of the mechanisms of peripheral tolerance, in addition to the suppression of self-reactive effector T cells by Tregs . The data presented in our current and previous studies have demonstrated cunning strategies of murine retrovirus to evade anti-viral CD8+ T cell immunity by modulating both central and peripheral tolerance. During the acute phase of infection, massively expanded virus-infected PD-L1hi erythroblasts disrupt the function of virus-specific effector CD8+ T cells in the periphery . Then, the virus disseminates to the thymus and induces viral antigen presentation by DCs and TECs just as if self-antigens are present. In fact, endogenous retroviral antigens potentially cross-reactive to the exogenous retroviruses are known to be present in the thymus and shape T cell responses to the exogenous retroviruses by inducing the negative selection of low-avidity virus-reactive T cells . On the other hand, the presentation of exogenously infecting viral antigens in the thymus inhibits subsequent production of virus-specific naïve CD8+ T cells as a source of functional memory CD8+ T cells in chronically infected animals as we have shown here for FV infection. Consequently, almost all virus-specific CD8+ T cells in FV-infected animals lack their effector functions. Although viral replication is controlled at low levels by the production of virus-neutralizing antibodies , mice chronically infected with FV are highly susceptible to challenge with FV-induced tumor cells against which CD8+ T cell response is required for effective elimination.