Abstract
Lymphocytic choriomeningitis virus (LCMV) is a paradigm-forming experimental system with a remarkable track record of contributing to the discovery of many of the fundamental concepts of modern immunology. The ability of LCMV to establish a chronic infection in immunocompetent adult mice was instrumental for identifying T cell exhaustion and this system has been invaluable for uncovering the complexity, regulators, and consequences of this state. These findings have been directly relevant for understanding why ineffective T cell responses commonly arise during many chronic infections including HIV and HCV, as well as during tumor outgrowth. The principal feature of exhausted T cells is the inability to elaborate the array of effector functions necessary to contain the underlying infection or tumor. Using LCMV to determine how to prevent and reverse T cell exhaustion has highlighted the potential of checkpoint blockade therapies, most notably PD-1 inhibition strategies, for improving cellular immunity under conditions of antigen persistence. Here, we discuss the discovery, properties, and regulators of exhausted T cells and highlight how LCMV has been at the forefront of advancing our understanding of these ineffective responses.
Highlights
Lymphocytic Choriomeningitis Virus (LCMV) and the Definition of T Cell ExhaustionSince its discovery in the mid-1930s [1,2] lymphocytic choriomeningitis virus (LCMV) has become a proven system for defining fundamental immunological concepts
The ability of LCMV to establish both acute and chronic infections together with the primacy of the T cell response for mediating viral clearance and causing lethal immunopathology, coupled with the power of mouse genetics, has enabled LCMV to be at the forefront of immunological research for decades
Exhaustion is distinct from other dysfunctional states such as anergy, which arises after incomplete priming of naïve T cells during their interactions with antigen presenting cells (APCs); central tolerance, such as that arising in neonatally LCMV-infected carrier mice which results in thymic deletion of virus-specific T cells; and peripheral tolerance where T cell activation is repressed against perceived self-antigens as a mechanism to prevent immune pathology [29]
Summary
Lymphocytic Choriomeningitis Virus (LCMV) and the Definition of T Cell Exhaustion. Since its discovery in the mid-1930s [1,2] lymphocytic choriomeningitis virus (LCMV) has become a proven system for defining fundamental immunological concepts. A central strength of the LCMV system is that many of the discoveries regarding both cellular and humoral immunity have been confirmed in humans These common immunological themes include the formation of effector and memory T cell subsets, the longevity of adaptive immunity, and the development of T cell exhaustion. L1079 residues is further illustrated by analyses of viral variants isolated from immunodeficient mice in which the parental acute Armstrong strain can establish a chronic infection due to the disabled immune response. Exhaustion is distinct from other dysfunctional states such as anergy, which arises after incomplete priming of naïve T cells during their interactions with antigen presenting cells (APCs); central tolerance, such as that arising in neonatally LCMV-infected carrier mice which results in thymic deletion of virus-specific T cells; and peripheral tolerance where T cell activation is repressed against perceived self-antigens as a mechanism to prevent immune pathology [29]. Many of the key concepts about immune exhaustion have been gleaned from studies using LCMV, they have been shown to be directly relevant to infections and pathologies in humans and have provided an informative foundation for better understanding immune mediated control in situations where the priming antigen persists
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