Journal Article

T cell responses to cytomegalovirus

Klenerman, Paul, Oxenius, Annette

2016

Overview

Key Points Cytomegalovirus (CMV) induces large populations of CD8 + T cells that retain effector functions, have an effector memory phenotype and home to peripheral organs. The phenomenon has been termed 'memory inflation' on the basis of longitudinal studies in mouse models. The CMV-specific T cell populations that undergo memory inflation are a subset of those that are primed, and they are maintained owing to persistence of the antigen. The viral peptides that drive these responses seem to be presented by non-professional antigen-presenting cells and are immunoproteasome independent. The expanded CD8 + T cell populations that are observed in CMV infection have a transcriptional profile that is different to that seen in 'exhausted' CD8 + T cells but is similar to that seen in T cells responding to other low-level persistent challenges, such as adenoviral vaccines, in both humans and mice. Using the adenoviral system, conventional T cell responses can acquire features of expanded CMV-specific T cell responses by modifying the peptide context. The CMV-induced CD8 + T cell responses are dependent on CD4 + T cell help and co-stimulatory signals. Such signals are probably required to support the recruitment of effector memory T cells from a pool of central memory T cells, although the precise nature and niche of the non-professional antigen-presenting cells involved are still ill-defined. In elderly populations, the marked expansion of CMV-specific T cells is associated with a failure to control the virus and increased levels of CMV-specific IgG, which are features that have been linked to adverse health outcomes in some large epidemiological studies. Although causal mechanisms have not been defined, local replication of CMV may influence vascular pathology through the activation of inflammatory pathways. Infection with cytomegalovirus induces an unusually high level of long-lasting memory T cells that have potent effector functions. Understanding how and why this occurs might help to improve responses to vaccination. Human cytomegalovirus (HCMV) establishes a latent infection that generally remains asymptomatic in immune-competent hosts for decades but can cause serious illness in immune-compromised individuals. The long-term control of CMV requires considerable effort from the host immune system and has a lasting impact on the profile of the immune system. One hallmark of CMV infection is the maintenance of large populations of CMV-specific memory CD8 + T cells — a phenomenon termed memory inflation — and emerging data suggest that memory inflation is associated with impaired immunity in the elderly. In this Review, we discuss the molecular triggers that promote memory inflation, the idea that memory inflation could be considered a natural pathway of T cell maturation that could be harnessed in vaccination, and the broader implications of CMV infection and the T cell responses it elicits.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/250/1619/554 / 631/250/2152/1566/1571 / 631/250/255/2514 / Aging - immunology / Aging - metabolism / Animals / Antigens / Biomedicine / Care and treatment / Complications and side effects / Cytomegalovirus / Cytomegalovirus - immunology / Cytomegalovirus infections / Cytomegalovirus Infections - genetics / Cytomegalovirus Infections - immunology / Cytomegalovirus Infections - metabolism / Cytomegalovirus Infections - virology / Cytomegaloviruses / Development and progression / Health aspects / Host-Pathogen Interactions - genetics / Host-Pathogen Interactions - immunology / Humans / Immune response / Immune system / Immunologic Memory / Immunology / Infections / Influence / Lymphocytes / Observations / Peptides / Physiological aspects / Properties / review-article / T cells / T-Cell Antigen Receptor Specificity - immunology / T-Lymphocyte Subsets - immunology / T-Lymphocyte Subsets - metabolism / T-Lymphocytes - immunology / T-Lymphocytes - metabolism