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Cytokine control of memory T-cell development and survival

Key Points

  • Common cytokine receptor γ-chain (γc) cytokines control the immune response at overlapping, as well as distinct, checkpoints, and the levels of expression of γc-cytokine receptors are differentially regulated during an immune response.

  • Interleukin-2 (IL-2), IL-7 and IL-15 exert diverse effects related to T-cell survival, activation and clonal expansion, and memory-cell development and maintenance.

  • IL-7 mediates the survival of naive and memory T cells.

  • Memory T-cell homeostasis can be affected by secondary encounter with antigen, bystander proliferation or attrition.

  • IL-15 is essential for the homeostatic proliferation of memory CD8+ T cells and maintenance of the steady-state level of CD8+ T-cell memory.

  • IL-15 might exert direct effects on memory CD8+ T cells or might act on other cell types, which subsequently regulate memory T-cell proliferation. IL-15 might also be presented by other cells to CD8+ T cells through interaction with the IL-15 receptor β-chain.

Abstract

Evidence has accumulated that cytokines have a fundamental role in the differentiation of memory T cells. Here, we follow the CD8+ T cell from initial activation to memory-cell generation, indicating the checkpoints at which cytokines determine the fate of the T cell. Members of the common cytokine-receptor γ-chain (γc)-cytokine family — in particular, interleukin-7 (IL-7) and IL-15 — act at each stage of the immune response to promote proliferation and survival. In this manner, a stable and protective, long-lived memory CD8+ T-cell pool can be propagated and maintained.

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Figure 1: Cytokines control T-cell differentiation checkpoints.
Figure 2: Members of the γc cytokine-receptor family are important for memory T-cell development.
Figure 3: Differential expression of cytokine-receptor subunits during the immune response.
Figure 4: Mechanisms involved in the maintenance of memory CD8+ T cells.
Figure 5: Alterations in memory T-cell homeostasis.
Figure 6: Direct and indirect effects of IL-15 on memory T-cell maintenance.

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Acknowledgements

Work in our laboratory is supported by grants from the National Institutes of Health.

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Correspondence to Leo Lefrançois.

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DATABASES

LocusLink

CD4

CD8

CD132

IFN-α/β

IFN-γ

IL-2

IL-2Rβ

IL-4

IL-7

IL-7Rα

IL-15

IL-15Rα

IL-21

Glossary

COMMON CYTOKINE RECEPTOR γ-CHAIN FAMILY

A family of cytokine receptors in which each receptor complex is composed of two or three subunits, with one of those subunits being the common cytokine receptor γ-chain (γc).

MHC CLASS I TETRAMERS

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

TOLL-LIKE RECEPTORS

(TLRs). A family of receptors that recognize conserved products unique to microorganisms (such as lipopolysaccharide). Stimulation through TLRs induces dendritic-cell maturation and activation, leading to optimal activation of the adaptive immune response. TLR-mediated events signal to the host that a microbial pathogen is present.

NON-LYMPHOID TISSUES

Any tissue that is not considered to be a primary or secondary lymphoid organ. Non-lymphoid tissues, such as lung, liver and intestine, harbour as many activated and memory T cells as do the secondary lymphoid tissues.

BCL-2-FAMILY MEMBERS

Mitochondrial proteins that increase or decrease the susceptibility of a cell to apoptosis. When levels of either BCL-2 or BCL-XL are increased, a cell is more resistant to cell death.

CD44

A cell-surface glycoprotein that is expressed by many cell types. Among CD8+ T cells, expression of CD44 is upregulated after activation and remains at high levels on memory T cells.

BROMODEOXYURIDINE

(BrdU). A thymidine analogue that is incorporated into DNA during DNA replication. In vivo or in vitro treatment with BrdU can allow the detection of dividing cells by intracellular staining with fluorescence-labelled BrdU-specific antibodies followed by flow cytometry.

5,6-CARBOXYFLUORESCEIN DIACETATE SUCCINIMIDYL ESTER

(CFSE). An intravital fluorescent dye that is equally distributed between daughter cells after each cell division, thereby allowing the division history of a cell to be determined (up to 8 divisions) by flow cytometry.

CD62L

Also known as L-selectin, this molecule binds to peripheral-node addressin on high endothelial venules and acts as a homing receptor allowing T cells to traffic to lymph nodes.

INTRACELLULAR CYTOKINE STAINING

An assay used to identify cells that produce cytokines in response to activation signals. Activated or memory T cells will produce cytokines after brief in vitro stimulation with antigen. While in culture, the secretion of these cytokines is blocked, allowing a sufficient quantity to build up intracellularly to allow detection using fluorescence-labelled cytokine-specific antibodies and flow cytometry.

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Schluns, K., Lefrançois, L. Cytokine control of memory T-cell development and survival. Nat Rev Immunol 3, 269–279 (2003). https://doi.org/10.1038/nri1052

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