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  • Review Article
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Lymphocide: cytokines and the control of lymphoid homeostasis

Nature Reviews Immunology volume 2, pages 817–830 (2002)Cite this article

Key Points

  • Lymphocytes are produced continually by primary organs and they proliferate steadily in peripheral lymphoid organs. However, except for during an immune response, the total number of lymphocytes remains fixed. This phenomenon is known as 'lymphoid homeostasis', which represents a balance between proliferation and cell death.

  • The main signals that regulate lymphocyte homeostasis are cytokines. Interleukin-7 (IL-7) and IL-15 are the best-characterized 'trophic' cytokines for the maintenance of several lymphocyte subsets, including naive and memory CD8+ T cells and natural killer cells.

  • There are many pathways to 'lymphocide'. The death pathway from cytokine deprivation is distinct from the pathways from death receptors such as FAS or from transforming growth factor-β or reactive oxygen species.

  • The binding of a cytokine to its receptor triggers signalling pathways that promote cell survival. One such survival pathway involves the activation of AKT by phosphatidylinositol 3-kinase, which is downregulated by phosphatase and tensin homologue (PTEN). No clear role for this pathway during lymphoid homeostasis has been established, although it can prolong the survival of cytokine-dependent cell lines after cytokine withdrawal.

  • Withdrawal of trophic cytokines can affect intracellular metabolism, by disrupting glucose metabolism and ATP synthesis, dysregulating cytosolic pH and compromising mitochondrial function. Such severe metabolic disruptions probably trigger later events in apoptosis, such as caspase activation, or might, in time, be fatal on their own.

  • Anti-apoptotic proteins (such as BCL-2) are induced by trophic cytokines. However, BCL-2 cannot account for all of the pro-survival activity of trophic cytokines because it has little effect on protection from cytokine withdrawal in lymphoid homeostasis.

  • Pro-apoptotic proteins such as BAX and BAK seem to mediate the death of memory CD8+ T cells after IL-7 or IL-15 withdrawal. Regulators of memory CD4+ T cells remain to be determined. The death proteins BIM and BAD might also contribute to the homeostatic death of lymphocytes.

Abstract

In a human, about 1011 excess peripheral lymphocytes die every day. This death process maintains a constant lymphocyte population size in the face of a continuous influx of new lymphocytes and the homeostatic proliferation of old ones. Death is triggered when a lymphocyte fails to acquire signals from survival factors, the availability of which, therefore, determines the size of the pool of lymphocytes. A lymphocyte acquires survival signals through receptors for cytokines, antigens, hormones and probably other extracellular factors. Here, we discuss current concepts of the intracellular signalling pathways for survival versus death that establish cytokine-regulated lymphocyte homeostasis.

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Figure 1: Forces that maintain lymphocyte homeostasis.
Figure 2: The lymphotrophin hypothesis.
Figure 3: Death from trophic-factor loss is distinct from death through FAS.
Figure 4: Signal-transduction pathways promoting lymphocyte survival.
Figure 5: Early death-inducing events after trophic-factor withdrawal.
Figure 6: The pro-apoptotic BCL-2-family members.

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Authors and Affiliations

  1. Laboratory of Molecular Immunoregulation, Center for Cancer Research, National Cancer Institute, Frederick, 21702-1201, Maryland, USA

    Annette R. Khaled & Scott K. Durum

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  1. Annette R. Khaled
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Correspondence to Scott K. Durum.

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DATABASES

Cancer.gov

leukaemia

lymphoma

InterPro

BH1–BH3

BH4

LocusLink

4-1BB

4-1BBL

AIF

AKT

APAF1

βc

B7

BAD

BAFF

BAK

BAX

BCL-2

BCL-W

BCL-XL

BID

BIK

BIM

BLK

BOK

caspase-3

caspase-7

caspase-8

caspase-9

caspase-10

CD28

CD40

CD40L

CREB

c-Rel

ERK

FAS

FASL

FKHRL1

FLICE

FLIP

γc

GLUT1

GLUT4

GM-CSF

GSK3

HRK

IL-2

IL-2Rα

IL-3

IL-4

IL-5

IL-6

IL-7

IL-7Rα

IL-9

IL-15

IL-15Rα

IL-21

JAK3

LC8

MCL1

MEK1

NHE

OMI

p38 MAPK

p85α

p90 RSK

p110

PI3K

PTEN

SHC

STAT5

TGF-β

TNF

TRAF1

TRAF2

Vav

XIAP

OMIM

ALPS

Glossary

5,6-CARBOXYFLUORESCEIN DIACETATE SUCCINIMIDYL ESTER

(CFSE). A stable green-fluorescent dye that can be used to label populations of cells homogeneously. When a cell divides, the fluorescence intensity decreases by 50%, and this allows cells that have divided a specific number of times to be visualized by flow cytometry. This reagent can measure ∼7–10 cell divisions successfully.

γC CYTOKINES

Cytokines with receptors that share the common cytokine-receptor γ-chain (CD132). These cytokines are all short-chain, four-helical bundles, and they include IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21.

REACTIVE OXYGEN SPECIES

(ROS). Oxygen radicals that are produced by the mitochondrial respiratory chain. In excess, they can cause intracellular and mitochondrial damage, which promotes cell death.

SMAD

(Sma and Mad proteins in Caenorhabditis elegans and Drosophila, respectively). SMAD proteins are downstream effectors of the TGF-β signalling cascade. These proteins transduce signals from the cell membrane to the nucleus, thereby initiating the transcription of target genes.

ACTIVATION-INDUCED CELL DEATH

(AICD). A process by which activated T cells undergo cell death through engagement of death receptors such as FAS or the TNF receptor, or the production of reactive oxygen species.

LYMPHOPAENIA

A deficiency of lymphocytes in the blood circulation.

14-3-3

A family of conserved proteins present in all eukaryotic organisms that are involved in such diverse cellular processes as apoptosis and stress, as well as intracellular signalling and cell-cycle regulation. 14-3-3 proteins function as adaptors in protein interactions and can regulate protein localization and enzymatic activity. Approximately 100 binding partners for the 14-3-3 proteins have been reported.

PHOSPHATASE AND TENSIN HOMOLOGUE

(PTEN). A phosphatidylinositol 3-phosphatase and tumour suppressor that dephosphorylates lipid phosphatidylinositol-3,4,5-triphosphates and antagonizes the activity of phosphatidylinositol 3-kinase.

PRE-T-CELL RECEPTOR

(pre-TCR). A receptor that is expressed on pre-T cells formed by the TCR β-chain and the invariant pre-Tα protein. This receptor complex includes CD3 proteins and transduces signals that allow further T-cell development.

INHIBITORS OF APOPTOSIS

(IAPs). A family of proteins that inhibit cell death by interfering with caspase activity. IAPs, such as XIAP and survivin, target distinct caspases. In addition, IAPs have other functions in cell-cycle regulation, protein degradation and signal transduction.

GLUCOSE TRANSPORTER PROTEINS

(GLUT). A family of GLUT proteins facilitate the transport of glucose across membranes, each member having a distinct tissue distribution and biochemical activity.

SODIUM/HYDROGEN EXCHANGER

(NHE). The NHE-family proteins are membrane-spanning electroneutral ion exchangers. The family includes six isoforms (NHE1–NHE6). Diverse effects of NHE1 include homeostasis of the internal pH, cell-volume regulation and interaction with the actin cortical network, which regulates adhesion, cell-shape determination, migration and proliferation.

MITOCHONDRIAL MEMBRANE POTENTIAL

The voltage difference across the mitochondrial inner membrane, with the outside being positive and the inside being negative, that generates the proton-motive force, driving the synthesis of ATP by the process of oxidative phosphorylation.

LYMPHOCYTOSIS

An increase in the number of lymphocytes in the blood, which is usually associated with chronic infections or inflammation.

APOPTOSOME

An apoptotic protein complex formed from the association of APAF1, cytochrome c and dATP with pro-caspase-9. Complex formation leads to the cleavage and activation of caspase-9, which activates caspase-3 and other effector caspases, leading to cell death.

APOPTOSIS-INDUCING FACTOR

(AIF). A protein found in the mitochondrial intermembrane. When released from mitochondria after loss of the mitochondrial outer membrane, AIF travels to the nucleus and activates a nuclease that degrades DNA.

OMI

A mitochondrial serine protease. When released from the mitochondrial intermembrane space, OMI enters the cytosol, where it enhances caspase-dependent apoptosis by blocking inhibitors. Caspase-independent cell death might result from its serine-protease activity.

SMAC/DIABLO

(second mitochondrial apoptosis-activating factor). Another protein found in the mitochondrial intermembrane. When released, SMAC binds IAPs, inhibiting their pro-survival functions. Complexes of SMAC and IAPs have decreased anti-apoptotic activity.

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Khaled, A., Durum, S. Lymphocide: cytokines and the control of lymphoid homeostasis. Nat Rev Immunol 2, 817–830 (2002). https://doi.org/10.1038/nri931

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