Role of lymphocytic choriomeningitis virus (LCMV) in understanding viral immunology: past, present and future

Abstract

Lymphocytic choriomeningitis virus (LCMV) is a common infection of rodents first identified over eighty years ago in St. Louis, MO, U.S.A. It is best known for its application in immunological studies. The history of LCMV closely correlates with the development of modern immunology. With the use of LCMV as a model pathogen several key concepts have emerged: Major Histocompatibility Complex (MHC) restriction, T cell memory, persistent infections, T cell exhaustion and the key role of immune pathology in disease. Given the phenomenal infrastructure within this field (e.g., defined immunodominant and subdominant epitopes to all T cell receptor specificities as well as the cognate tetramers for enumeration in vivo) the study of LCMV remains an active and productive platform for biological research across the globe to this day. Here we present a historical primer that highlights several breakthroughs since the discovery of LCMV. Next, we highlight current research in the field and conclude with our predictions for future directions in the remarkable field of LCMV research.

Figure 1

Tree of knowledge as disseminated by the lymphocytic choriomeningitis virus (LCMV) model system. This tree depicts a partial history of significant research milestones with the LCMV model system. The conceptual and/or experimental relationship between different discoveries is represented by uni-directional arrows. Green font is used to represent the first part of this review, concepts in persistent viral infection. Purple is used to highlight the second section, T cell immunity. Blue is used to represent the third section, innate immunity. Lastly, red represents the fourth and final section of immune dysfunction. Of note, certain scientific ideas (e.g., “T cell exhaustion”) are conceptually and experimentally derived from multiple lines of research and thus relevant to multiple sections of this review and our understanding of viral immunology. However, for simplicity they are represented by a single color.

Figure 2

The Discovery of Major Histocompatibility Complex (MHC) restriction. These experiments were completed and published in 1974. Rolf Zinkernagel and Peter Doherty harvested splenocytes containing viral specific cytotoxic T lymphocytes (CTL) from infected mouse strain A. These CTL were then mixed in vitro with either C3H mouse fibroblasts or macrophages derived from different strains, infected with LCMV or uninfected, and labeled with Chromium-51 (Cr-51). CTL killing of target cells was assessed by release of Cr-51. These experiments demonstrated that LCMV specific CTL are “MHC restricted” and thus only lyse cells carrying the same MHC as the strain generated from those CTL [30].

Figure 3

Schematic of epitope-specific CD4 and CD8 T cell response from acute activation to memory. Data adapted from Homann et al. 2001 [44]. Splenocytes were collected on the day post infection indicated. MHC tetramer staining was performed to enumerate T cells specific to the LCMV GP61 epitope- (CD4 T cell specific; blue line) as well as the LCMV CD8 T cell specific epitopes, GP33 (red line) and NP396 (black line).

Figure 4

Heterologous immunity. This figure shows the relationship of heterologous immunity between LCMV and other viruses. These experiments were performed using C57BL/6 mice. The black filled arrows indicate a protective effect between the first infection (base of arrow) and the challenge infection (head of arrow). In some cases this protection from heterologous immunity is bi-directional as shown. On the contrary, the unfilled arrow depicts an enhancement of disease when infection of influenza A precedes LCMV infection.