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During recent years, evidence has emerged that immune privileged sites such as the CNS and the retina may be more integrated in the systemic response to infection than was previously believed. In line with this, it was recently shown that a systemic acute virus infection leads to infiltration of CD8 T cells in the brains of immunocompetent mice. In this study, we extend these findings to the neurological tissue of the eye, namely the retina. We show that an acute systemic virus infection in mice leads to a transient CD8 T cell infiltration in the retina that is not directed by virus infection inside the retina. CD8 T cells were found throughout the retinal tissue, and had a high expression of CXCR6 and CXCR3, as also reported for tissue residing CD8 T cells in the lung and liver. We also show that the pigment epithelium lining the retina expresses CXCL16 (the ligand for CXCR6) similar to epithelial cells of the lung. Thus, our results suggest that the retina undergoes immune surveillance during a systemic infection, and that this surveillance appears to be directed by mechanisms similar to those described for non-privileged tissues., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Paskeviciute, Chen, Xu, Honoré, Vorum, Sørensen, Christensen, Thomsen, Nissen and Steffensen.)

The host counters a viral infection through a complex response made up of components belonging to both the innate and the adaptive immune system. In this report, we review the mechanisms underlying this response, how it is induced and how it is co-ordinated. As cell-cell communication represents the very essence of immune system physiology, a key to a rapid, efficient and optimally regulated immune response is the ability of the involved cells to rapidly shift between a stationary and a mobile state, combined with stringent regulation of cell migration during the mobile state. Through the co-ordinated recruitment of different cell types intended to work in concert, cellular co-operation is optimized particularly under conditions that may involve rare cells. Consequently, a major focus is placed on presenting an overview of the co-operative events and the associated cell migration, which is essential in mounting an efficient host response and co-ordinating innate and adaptive immunity during a primary viral infection.

Experiments have established that CTLs do not require continuous antigenic stimulation for expansion. Instead, responses develop by a process of programmed proliferation which involves approximately 7-10 antigen-independent cell divisions, the generation of effector cells and the differentiation into memory cells. The effect of this program on the infection dynamics and the advantages gained by the program have, however, not been explored yet. We investigate this with mathematical models. We find that more programmed divisions can make virus clearance more efficient because CTL division continues to occur independent from antigenic stimulation when virus load drops to low levels. This results in stronger effector activity at low virus loads, and in a higher chance of virus extinction. On the other hand, the more programmed divisions occur, the less efficient the response is at preventing high acute virus loads and thus acute symptoms. The reason is that the programmed divisions are independent from antigenic stimulation, and an increase in virus load does not speed up the rate of CTL expansion. We hypothesize that the 7-10 programmed divisions observed in vivo represent an optimal solution to this trade-off which maximizes the chances to clear, while preventing excessive acute pathology. If the CTLs fail to clear the virus, however, we find that the properties of the programmed proliferation model are very similar to those derived from models which assume continuous antigenic stimulation. We discuss these results in the context of data from murine virus infections and explore implications for virus dynamics in CD4 helper-deficient hosts.

CD8 T-cell or cytotoxic T-lymphocyte responses develop through an antigen-independent proliferation and differentiation program. This is in contrast to the previous thinking, which was that continuous antigenic stimulation was required. This Opinion discusses why nature has chosen the proliferation program and how it compares to continuous stimulation. Although the two mechanisms should not lead to significantly different dynamics during chronic infection, they do make a difference in acute infection. We argue that programmed proliferation is better at clearance, whereas continuous stimulation is better at limiting acute symptoms. The 7-10 programmed cell divisions observed in vivo might be an optimization of this trade-off. We also discuss the conditions under which the program does or does not require CD4 T-cell help for clearance.

Antiviral immune effector mechanisms can be divided broadly into lytic and nonlytic components. We use mathematical models to investigate the fundamental question of which type of response is required to combat different types of viral infection. According to our model, the relative roles of the two types of component depend on the cytopathicity of the virus relative to its rate of replication. If the viral cytopathicity is low relative to the rate of viral replication, the model predicts that a combination of lytic and nonlytic effector mechanisms is likely to be required to resolve the disease, particularly if the virus replicates at a fast rate. By contrast, if viral cytopathicity is high relative to the replication rate of the virus, then lytic and nonlytic mechanisms can, in principle, resolve the infection independently. We discuss our findings in the context of specific viral infections and use our model to interpret empirical data.

The CC chemokine receptor CCR5 is an important coreceptor for human immunodeficiency virus (HIV), and there is a major thrust to develop anti-CCR5-based therapies for HIV-1. However, it is not known whether CCR5 is critical for a normal antiviral T-cell response. This study investigated the immune response to lymphocytic choriomeningitis virus in mice lacking CCR5 (CCR5(-/-) mice). This infection is a classical model for studying antiviral immunity, and influx of CCR5-expressing CD8(+) T cells and macrophages is essential for both virus control and associated immunopathology. Results showed that the virus-induced clonal expansion of antigen-specific T cells was augmented in CCR5(-/-) mice especially with regard to the CD4(+) subset. Despite absence of CCR5, intracerebral infection invariably resulted in lethal T cell-mediated meningitis, and quantitative and qualitative analysis of the inflammatory exudate cells did not reveal any significant differences between gene-targeted mice and wild-type controls. CCR5 was also found to be redundant regarding the ability to eliminate virus from internal organs. Using delayed-type hypersensitivity to evaluate CD8(+) T cell-mediated inflammation, no significant influence of CCR5 was found, not even when viral peptide was used as local trigger instead of live virus. Finally, long-term CD8(+) T cell-mediated immune surveillance was efficiently sustained in CCR5(-/-) mice. Taken together, these results indicate that expression of CCR5 is not critical for T cell-mediated antiviral immunity, and this molecule may therefore constitute a logic and safe target for anti-HIV therapies.

T-cells play an important role in controlling viral infections inside the CNS. To study the role of the chemokine receptor CXCR3 in the migration and positioning of virus-specific effector T-cells within the brain, CXCR3-deficient mice were infected intracerebrally with lymphocytic choriomeningitis virus (LCMV). Analysis of the induction phase of the antiviral CD8+ T-cell response did not reveal any immune defects in CXCR3-deficient mice. Yet, when mice were challenged with LCMV intracerebrally, most CXCR3-deficient mice survived the infection, whereas wild-type mice invariably died from CD8+ T-cell-mediated immunopathology. Quantitative analysis of the cellular infiltrate in CSF of infected mice revealed modest, if any, decrease in the number of mononuclear cells recruited to the meninges in the absence of CXCR3. However, immunohistological analysis disclosed a striking impairment of CD8+ T-cells from CXCR3-deficient mice to migrate from the meninges into the outer layers of the brain parenchyma despite similar localization of virus-infected target cells. Reconstitution of CXCR3-deficient mice with wild-type CD8+ T-cells completely restored susceptibility to LCMV-induced meningitis. Thus, taken together, our results strongly point to a critical role for CXCR3 in the positioning of effector T-cells at sites of viral inflammation in the brain. [ABSTRACT FROM AUTHOR]

T cell mediated immunity and in particular CD8+ T cells are pivotal for the control of most viral infections. T cells exclusively exert their antiviral effect through close cellular interaction with relevant virus-infected target cells in vivo. It is therefore imperative that efficient mechanisms exist, which will rapidly direct newly generated effector T cells to sites of viral replication. In the present report we have reviewed our present knowledge concerning the molecular interactions, which are important in targeting of effector CD8+ T cells to sites of viral infection. [Copyright &y& Elsevier]

The role of soluble receptors for TNF-α (sTNF-Rs) as markers of virus-induced host responses was studied by the use of murine model infections. A marked elevation in serum levels of sTNF-R75, but not sTNF-R55, was found 1 day after infection with vesicular stomatitis virus (VSV). In mice infected with lymphocytic choriomeningitis virus (LCMV), an early increase was also revealed, but peak levels of sTNF-R75 were observed later temporally related to maximal T cell-mediated anti-viral activity. Analysing different well characterized knockout mice, it was found that elevated release of sTNF-R75 into serum early after VSV infection was independent of T cells, whereas interferon (IFN)-α/β seemed to be a major mediator. In contrast, increased release of sTNF-R75 into serum 8 days post-LCMV infection was mediated via T cells but independently of both CD40 ligand and IFN-γ. A simple correlation between release of sTNF-Rs in vivo and macrophage activation in vitro was not present. These findings indicate that sTNF-R75 is indeed a sensitive marker of both innate and specific cell-mediated host reactivity during viral infection, but it is not correlated to a single immunological parameter. [ABSTRACT FROM AUTHOR]

Suppressors of cytokine signaling (SOCS) proteins are intracellular proteins that inhibit cytokine signaling in a variety of cell types. A number of viral infections have been associated with SOCS upregulation; however, not much is known about the mechanisms regulating SOCS expression during viral infection. In this study, we used two pathologically distinct intracerebral (i.c.) infection models to characterize temporal and spatial aspects of SOCS expression in the virus-infected central nervous system (CNS), and by employing various knockout mouse models, we sought to identify regulatory mechanisms that may underlie a virus induced upregulation of SOCS in the CNS. We found that i.c. infection with either lymphocytic choriomeningitis virus (LCMV) or yellow fever virus (YF) results in gradual upregulation of SOCS1/3 mRNA expression peaking at day 7 postinfection (p.i.). In the LCMV model, SOCS mRNA was expressed in brain resident cells, including astrocytes and some neurons, and for SOCS1 in particular this upregulation was almost entirely mediated by gamma interferon (IFN-) produced by infiltrating T cells. After infection with YF, we also found SOCS expression to be upregulated in brain resident cells with a peak on day 7 p.i., but in this model, the upregulation was only partially dependent on IFN- and T cells, indicating that at least one other mediator was involved in the upregulation of SOCS following YF infection. We conclude that virus-induced inflammation of the CNS is associated with upregulation of SOCS1/3 mRNA expression in brain resident cells and that at least two distinctive pathways can lead to this upregulation. [ABSTRACT FROM AUTHOR]