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Review
. 2021 Sep 29;13(10):1951.
doi: 10.3390/v13101951.

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

Caleb J Studstill  1 , Bumsuk Hahm  1
Affiliations
Review

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

Caleb J Studstill et al. Viruses. .

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.

Keywords: LCMV; T cell exhaustion; T cell immunology; immunology models; persistent viral infections; viral immunology.

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Conflict of interest statement

The authors declare no conflict of interest for this work.

Figures

Figure 1
Figure 1
Infection of mice with differing LCMV strains leads to variable T cell responses impacting viral clearance. The prototype strain of LCMV, Armstrong 53b (Arm), readily infects mice. However, a strong host CD8+ T cell response and an ancillary CD4+ T cell response are able to clear the viral infection quickly. However, a variant strain of LCMV, Clone 13 (Cl 13), has two functional amino acid (aa) changes, which affect the virus’s ability to bind to its receptor and replicate in the host cell. These changes instigate a progressive exhaustion phenotype in both CD8+ and CD4+ T cells during LCMV Cl 13 infection. Studies have revealed that early, high antigen levels, the production of immunosuppressive cytokines, and disruption of lymphoid tissues promote epigenetic and transcriptional changes in T cells. These regulatory events lead to and occur in conjunction with increases in inhibitory receptor levels on exhausted T cells. Ultimately, exhausted T cells lose their ability to function and proliferate allowing the virus to persist in the host.
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