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The role of models in understanding CD8+ T-cell memory

Nature Reviews Immunology volume 5, pages 101–111 (2005)Cite this article

Key Points

  • Immunological memory — the ability to 'remember' previously encountered pathogens and respond faster on re-exposure — is a central feature of the immune response of vertebrates. We outline how mathematical models have contributed to our understanding of CD8+ T-cell memory.

  • Mathematical models can help with the following: estimating parameters of immune responses, understanding non-linear processes, discriminating between different hypotheses and predicting features of immune responses for long time periods.

  • Estimating parameters: mathematical models can help to estimate parameters that cannot be measured directly. These include the precursor frequency of naive CD8+ T cells and the rates of clonal expansion and clonal contraction of these cells during the primary immune response after exposure to a pathogen.

  • Understanding non-linear processes: mathematical models are a valuable tool for understanding the complex non-linear interactions that characterize biological systems. We show how models have allowed us to consider the combined effects of homeostasis, bystander stimulation and crossreactive stimulation on the longevity of immune memory.

  • Discriminating between different hypotheses: mathematical models can help us to discriminate between alternative hypotheses. We describe how models have helped to discriminate between different pathways for the differentiation of CD8+ T cells during a primary immune response.

  • Predicting for long time-scales: mathematical models can be a useful tool for predicting phenomena that occur for long time periods. For example, after further development and testing, it might be possible to use models that allow us to rapidly predict the effect of different factors on the longevity of memory during the human lifespan.

Abstract

Immunological memory — the ability to 'remember' previously encountered pathogens and respond faster on re-exposure — is a central feature of the immune response of vertebrates. We outline how mathematical models have contributed to our understanding of CD8+ T-cell memory. Together with experimental data, models have helped to quantitatively describe and to further our understanding of both the generation of memory after infection with a pathogen and the maintenance of this memory throughout the life of an individual.

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Figure 1: Immunological memory can be divided into distinct phases with different time-scales.
Figure 2: The consequences of bystander and crossreactive stimulation for the number of memory cells of different lineages in the absence and presence of homeostasis.

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Acknowledgements

We thank A. Handel for helpful comments. R. Antia and R. Ahmed are supported by the National Institutes of Health (United States).

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Authors and Affiliations

  1. Department of Biology, Emory University, Atlanta, 30322, Georgia, USA

    Rustom Antia & Vitaly V. Ganusov

  2. Emory Vaccine Center, Emory University, Atlanta, 30322, Georgia, USA

    Rafi Ahmed

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  1. Rustom Antia
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Correspondence to Rustom Antia.

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DATABASES

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CD4

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IL-7

IL-15

Infectious Disease Information

LCMV

Glossary

BURNET'S THEORY OF CLONAL SELECTION

This theory states that each lymphocyte expresses antigen receptors of a single type and that antigen selects for the proliferation of clones that express receptors capable of binding the antigen.

IMMUNODOMINANCE

The result of antigen(s) or epitopes within a complex mixture (such as a whole virus) being preferentially recognized or reacted against during an immune response.

BROMODEOXYURIDINE

(5-Bromo-2-deoxyuridine, BrdU). A thymidine analogue that is incorporated into DNA on replication, allowing tracking of cells that have divided.

ORDINARY DIFFERENTIAL EQUATION

A differential equation that involves ordinary derivatives of one or more dependent variables with respect to a single independent variable. For example, dX/dt = rX describes the exponential growth of a population of cells, X (the dependent variable), as a function of time, t (the independent variable).

CFSE

(5,6-Carboxyfluorescein diacetate succinimidyl ester). A membrane-permeable dye that covalently attaches to free amines of cytoplasmic proteins vitro. After cell division, the concentration of the label halves with each division, allowing eight to ten successive divisions to be tracked by flow cytometry.

BEST FIT

A procedure that estimates the parameters in a model by minimizing the differences between the predictions of the model and experimental data.

BYSTANDER STIMULATION

The activation and proliferation of cells after exposure to a pathogen in a manner that is independent of their antigenic specificity.

CROSSREACTIVE STIMULATION

The activation and oliferation of (antigen-specific) cells that previously clonally expanded in response to an unrelated antigen or pathogen.

HOMEOSTATIC REGULATION

The regulation of the total number of cells of a given type, such as CD8+ memory T cells.

TELOMERES

Regions of highly repetitive DNA at the end of linear eukaryotic chromosomes. They protect the ends of the chromosome from shortening on replication.

AFFINITY MATURATION

The increase in the average affinity of an immune response for an antigen. This occurs with time or after repeated exposure to an antigen.

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Antia, R., Ganusov, V. & Ahmed, R. The role of models in understanding CD8+ T-cell memory. Nat Rev Immunol 5, 101–111 (2005). https://doi.org/10.1038/nri1550

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