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  • Review Article
  • Published:

T cell responses to cytomegalovirus

Nature Reviews Immunology volume 16, pages 367–377 (2016)Cite this article

Subjects

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.

Abstract

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.

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Figure 1: Non-classical CD8+ T cell memory and CMV infection.
Figure 2: Dynamic features of memory inflation.
Figure 3: Requirements for memory inflation.
Figure 4: CMV, memory inflation and ageing.

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Acknowledgements

This work was supported by the Swiss Federal Institute of Technology in Zürich (ETH Zürich) and the Swiss National Science Foundation (310030_146140 to A.O.), the UK Medical Research Council (MRC), the Wellcome Trust (WT 091663MA to P.K.), the NIHR Biomedical Research Centre Oxford, Oxford Martin School, an NIHR Senior Investigator award (to P.K.) and the US NIH (U19AI082630). The authors are grateful to the members of the Oxenius and Klenerman groups, especially N. Torti, J. Thom, N. Baumann, L. Li, A. Highton, C. Hutchings and J. Colston for their contributions.

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Authors and Affiliations

  1. Peter Medawar Building for Pathogen Research and Translational Gastroenterology Unit, NIHR Biomedical Research Centre, University of Oxford, Oxford, OX1 3SY, UK

    Paul Klenerman

  2. Institute of Microbiology, Swiss Federal Institute of Technology (ETH) Zürich, Zürich, 8093, Switzerland

    Annette Oxenius

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  1. Paul Klenerman
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Correspondence to Paul Klenerman.

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Glossary

MHC class I tetramers

Biotinylated monomeric MHC class I molecules that are folded with a specific peptide in the binding groove and tetramerized with a fluorescently labelled streptavidin molecule. Tetramers bind to T cells expressing T cell receptors that are specific for the cognate peptide.

ELISpot assays

(Enzyme-linked immunosorbent spot assays). A method based on antibody capture and used to assess the numbers of CD4+ and CD8+ T cells that secrete a particular cytokine (often interferon-γ).

Central memory T cells

(TCM cells). Antigen-experienced T cells expressing cell surface receptors rthat are equired for homing to secondary lymphoid organs. These cells are generally thought to be long-lived and can serve as precursors for effector T cells in recall responses.

Effector memory T cells

(TEM cells). Antigen-experienced T cells that lack lymph node-homing receptors but express receptors that enable homing to inflamed tissues. TEM cells can exert immediate effector functions without the need for further differentiation.

Mass cytometry

Flow cytometry using antibodies that are tagged with heavy metal ions, which are detected by mass spectrometry (as opposed to classical flow cytometry, which uses antibodies tagged with fluorophores and optical detection). Mass cytometry allows large numbers of phenotypic markers to be assessed simultaneously on single cells.

T cell exhaustion

The condition of functionally impaired antigen-specific T cells, typified by increased surface expression of programmed cell death protein 1 and other co-inhibitory receptors, which occurs in the context of a persistently high antigen load. The defects in effector T cell function include a progressive decrease in their ability to produce cytokines, loss of proliferative capacity and decreased cytotoxicity, and can result in apoptotic cell death.

Tissue-resident memory T cells

(TRM cells). Cells that are generated primarily in non-lymphoid tissues and stably reside in these tissues while being disconnected from the circulation, where they provide immediate protection against local infections.

Spread-defective single round virus

A virus that can infect cells but cannot produce fully productive infectious particles and propagate in vivo. It nevertheless expresses viral antigens in the infected cell.

Immunoproteasome

The standard proteasome is composed of 14 α- and β-subunits, of which three (β1, β2 and β5) are involved in peptide-bond cleavage. Interferon-γ induces the expression of the immunosubunits β1i, β2i and β5i, which can replace the catalytic subunits of the standard proteasome to generate the immunoproteasome, which has distinct cleavage-site preferences.

Public TCRs

T cell receptors (TCRs) that are present and dominant in immune responses to a specific epitope in the majority of individuals.

Private TCRs

T cell receptors (TCRs) that are present and dominant in immune responses to a specific epitope; these immune responses are rarely observed in the majority of individuals.

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Klenerman, P., Oxenius, A. T cell responses to cytomegalovirus. Nat Rev Immunol 16, 367–377 (2016). https://doi.org/10.1038/nri.2016.38

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