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⇱ Shaping and reshaping CD8+ T-cell memory | Nature Reviews Immunology

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Key Points

  • Shortly after infection and/or vaccination, rare, antigen-specific CD8+ T cells encounter mature antigen-expressing dendritic cells (DCs), become activated and undergo extensive expansion in numbers following a 'programme' that is largely independent of the duration of the infection and/or functional antigen that is displayed. Most of the primary effector CD8+ T cells die during a programmed contraction phase and the surviving CD8+ T cells initiate the heterogeneous memory pool that slowly undergoes additional phenotypic and functional changes with time.

  • Proliferative expansion, phenotype, and function of CD8+ T-cell responses to infection are altered when the number of T-cell receptor (TCR)-transgenic CD8+ T cells transferred is sufficiently high to prevent the endogenous CD8+ T-cell response to the same epitope. The specific number of TCR-transgenic T cells that can be used to mimic the endogenous response may be influenced by the affinity of the TCR, the number of endogenous precursors and the pathogen or vaccination method used, and must be empirically determined for each experimental model.

  • The requirements for memory CD8+ T-cell maintenance and the functional characteristics of the CD8+ T-cell memory populations are dramatically different following persistent infection (that is, when antigen and pathogens are not cleared from the host) compared with acute infection.

  • Pro-inflammatory cytokines, for example type I interferons (IFNs), IFNΞ³ or interleukin-12, can act directly on responding CD8+ T cells during the expansion and contraction phases of CD8+ T-cell response to infection to affect crucial aspects of memory CD8+ T-cell generation.

  • The early inflammatory milieu dictates the rate at which CD8+ T cells acquire phenotypic and functional characteristics of memory suggesting that the process of memory CD8+ T-cell generation that depends on the nature of the pathogen or vaccination strategy used to elicit the response and that select aspects of memory CD8+ T-cell generation may be manipulable.

  • The characteristics of secondary memory CD8+ T cells are quite different than the primary CD8+ T-cell populations. They undergo protracted contraction, exhibit substantially delayed upregulation of central memory CD8+ T-cell characteristics, show decreased memory turnover (compared with primary memory CD8+ T cells) and exhibit (on per cell basis) enhanced protection against pathogen re-encounter.

Abstract

The ability to develop and sustain populations of memory T cells after infection or immunization is a hallmark of the adaptive immune response and a basis for protective vaccination against infectious disease. Technical advances that allow direct ex vivo identification and characterization of antigen-specific CD8+ T cells at various stages of the response to infection or vaccination in mouse models have fuelled efforts to characterize the factors that control memory CD8+ T-cell generation. Here, we dissect the input signals that shape the characteristics of the memory CD8+ T-cell response and discuss how manipulation of these signals has the potential to reshape CD8+ T-cell memory and improve the efficacy of vaccination.

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Figure 1: CD8+ T-cell response to infection and/or vaccination.
The alternative text for this image may have been generated using AI.
Figure 2: Influence of TCR-transgenic precursor frequency on important attributes of the CD8+ T-cell response to infection.
The alternative text for this image may have been generated using AI.
Figure 3: Memory CD8+ T-cell maintenance after acute or chronic infection.
The alternative text for this image may have been generated using AI.
Figure 4: Inflammatory cytokines and CD8+ T-cell homeostasis after infection.
The alternative text for this image may have been generated using AI.
Figure 5: Inflammation regulates the progression of CD8+ T cells to memory.
The alternative text for this image may have been generated using AI.
Figure 6: Primary and secondary CD8+ T-cell memory.
The alternative text for this image may have been generated using AI.

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Acknowledgements

We wish to thank Dr S. Perlman for critical reading of this manuscript. We apologize to those colleagues whose work we could not cite owing to space limitations. Work in the Harty laboratory is supported by grants from the National Institutes of Health, USA.

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Authors and Affiliations

  1. Department of Microbiology and Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa, USA

    John T. Harty

  2. Department of Pathology, University of Iowa, Iowa City, Iowa, USA

    Vladimir P. Badovinac

Authors
  1. John T. Harty
  2. Vladimir P. Badovinac

Corresponding author

Correspondence to John T. Harty.

Glossary

MHC class I tetramers

A soluble tetrahedral complex artificially generated by using a fluorochrome-coupled avidin to join four biotinylated MHC class I molecules with a peptide of interest and Ξ²2-microglobulin. The resulting MHC class I tetramer can be used as a reagent to identify antigen-specific CD8+ T-cell populations.

Intracellular cytokine staining

(ICS). A tool used for the analysis of the ability of T cells to produce a cytokine in response to a specific stimulus, such as peptide stimulation. In this assay, the usual cytokine secretion pathway is paralyzed and intracellular accumulation of the cytokine is monitored by antibody staining and FACS analysis.

OT-I mouse model

Mice in which the CD8 T cells have a transgenic rearranged T-cell receptor (VΞ±2, VΞ²5) that recognizes a peptide (OVA257–264) derived from chicken albumin in the context of H2-Kb. It can be used to study the response of CD8+ T cells to antigen.

T-bet

A member of the T-box family of transcription factors. It is a master switch in the development of T helper 1 (TH1)-cell responses, through its ability to regulate expression of the interleukin-12 receptor, inhibit signals that promote TH2-cell development and promote the production of interferon-Ξ³.

B-cell-lymphoma-2 family

(BCL-2 family). A family of proteins that contain at least one BCL-2-homology domain (BH). The family is classified into three groups: anti-apoptotic multidomain proteins, such as BCL-2, BCL-XL and MCL1 (myeloid-cell leukaemia sequence 1), which contain four BHs; pro-apoptotic multidomain proteins, such as BAX (BCL-2-associated X protein) and BAK (BCL-2 antagonist/killer), which contain three BHs; and a pro-apoptotic subfamily of proteins that contain only one BH, the BH3-only proteins.

Activation-induced cell death

(AICD). A form of regulated cell death that is induced during lymphocyte activation.

P14 mice

Transgenic mice of which the T cells recognize a peptide derived from lymphocytic choriomeningitis virus in the context of H2-Db.

Prime–boost vaccination

When a single application of a vaccine is insufficient, repeated immunizations are administered using the same vaccine preparation (homologous prime boost) or using different vaccine preparations (heterologous prime boost) to sequentially stimulate a better immune response. Prior exposure to one strain causes an antibody T-cell response to shared epitopes following exposure to a second strain.

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Harty, J., Badovinac, V. Shaping and reshaping CD8+ T-cell memory. Nat Rev Immunol 8, 107–119 (2008). https://doi.org/10.1038/nri2251

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