Chronic LCMV Infection Is Fortified with Versatile Tactics to Suppress Host T Cell Immunity and Establish Viral Persistence

Abstract

Ever since the immune regulatory strains of lymphocytic choriomeningitis virus (LCMV), such as Clone 13, were isolated, LCMV infection of mice has served as a valuable model for the mechanistic study of viral immune suppression and virus persistence. The exhaustion of virus-specific T cells was demonstrated during LCMV infection, and the underlying mechanisms have been extensively investigated using LCMV infection in mouse models. In particular, the mechanism for gradual CD8+ T cell exhaustion at molecular and transcriptional levels has been investigated. These studies revealed crucial roles for inhibitory receptors, surface markers, regulatory cytokines, and transcription factors, including PD-1, PSGL-1, CXCR5, and TOX in the regulation of T cells. However, the action mode for CD4+ T cell suppression is largely unknown. Recently, sphingosine kinase 2 was proven to specifically repress CD4+ T cell proliferation and lead to LCMV persistence. As CD4+ T cell regulation was also known to be important for viral persistence, research to uncover the mechanism for CD4+ T cell repression could help us better understand how viruses launch and prolong their persistence. This review summarizes discoveries derived from the study of LCMV in regard to the mechanisms for T cell suppression and approaches for the termination of viral persistence with special emphasis on CD8+ T cells.

Single-cell RNA sequencing reveals the dynamics and heterogeneity of lymph node immune cells during acute and chronic viral infections

“…The humoral immune response mediated by B cells plays a critical role in host defense against a variety of pathogens through secreting antibodies by plasma cells ( 52 , 53 ). In this study, chronic infection elicited more robust germinal center B-cell responses and antibody production than acute infection, consistent with previous studies ( 11 ). Surprisingly, the proportion of MALT B cells in chronic infection was significantly higher than that in acute infection on 8 dpi.…”

“…With the help of Tfh cells in the light zone of GCs, B cells differentiate into high-affinity antibody-secreting plasma cells and resultant memory B cells ( 55 , 56 ). Consistent with previous studies ( 11 ), our study showed that chronic infection induces a more robust germinal center B-cell response and higher production of antibody-producing plasma cells than acute infection. Overall, the B-cell immune response was more intense in chronic infection; however, it failed to clear the viruses once persistent infection was established, which deserves further exploration.…”

NK‐cell exhaustion, B‐cell exhaustion and T‐cell exhaustion—the differences and similarities

“…T‐cell suppression has frequently been used interchangeably with T‐cell exhaustion, causing considerable confusion. T‐cell suppression with decreased T‐cell functionality can be caused by multiple factors, including the influence of cytokines including IL‐10 from dendritic cells and exhausted CD4 T‐cells, interferon‐α and interferon‐β, and TGF‐β secreted by regulatory T‐cells or myeloid‐derived suppressor cells [33,34]. Furthermore, because CD8 T‐cells share several lymphocyte characteristics with NK‐cells, T‐cell suppression is very probable when there is tissue hypoxia (reduced oxygen); neuroendocrine activation; a hypercoagulable state (e.g.…”

“…and TGF-β secreted by regulatory T-cells or myeloidderived suppressor cells [33,34]. Furthermore, because CD8 T-cells share several lymphocyte characteristics with NK-cells, T-cell suppression is very probable when there is tissue hypoxia (reduced oxygen); neuroendocrine activation; a hypercoagulable state (e.g.…”

Protective versus Pathogenic Type I Interferon Responses during Virus Infections

“…The LCMV variant Clone 13 (Cl 13) infection model has been widely used for revealing mechanisms for T cell suppression and virus persistence [ 69 , 70 , 71 ]. Following LCMV Cl 13 infection, virus-specific T cells develop but gradually lose their functionalities, as evidenced by the substantially diminished capabilities to produce antiviral cytokines, such as IFN-γ and TNF-α, to display cytotoxic activity with granzymes and perforin secretion, as well as to proliferate in response to antigenic restimulation.…”