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Interleukin-7 receptor expression: intelligent design

Key Points

  • Interleukin-7 (IL-7) is required, and limiting, for T-cell development and survival.

  • IL-7 production by stromal cells in lymphoid tissues is constitutive.

  • The amount of available IL-7 is proposed to be significantly reduced by T-cell consumption.

  • IL-7 receptor expression varies dramatically during the life of a T cell. In the thymus, it is expressed at the double-negative stage, not expressed at the double-positive stage, and then re-expressed at the single-positive stage. In the periphery, it is expressed by naive T cells, but not by activated T cells, and is re-expressed by memory T cells. Naive T cells also turn off receptor expression transiently after IL-7 stimulation.

  • This dramatic downregulation of IL-7 receptor expression is proposed to have two benefits: first, the T cell at these discrete stages has alternative survival stimuli (such as antigen); second, the T cell 'altruistically' stops consuming IL-7, leaving more for its neighbouring cells.

Abstract

Interleukin-7 (IL-7) is produced by stromal cells in lymphoid tissues and is required for the development of T cells and for their persistence in the periphery. Unlike many other cytokines that act on lymphocytes, IL-7 production by stromal cells is not substantially affected by extrinsic stimuli. So, the amount of available IL-7 protein is thought to be regulated by the rate that it is scavenged by T cells. As we review here, there is mounting evidence indicating that the amount of IL-7 receptor expressed on a cell not only determines how vigorously the cell responds to IL-7, but it can also determine how efficiently the cell consumes IL-7 and, therefore, affect the supply of this limiting resource in the niche.

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Figure 1: Expression of interleukin-7 receptor α-chain in the lymphoid lineage.
Figure 2: Concepts of interleukin-7 consumption.
Figure 3: The interleukin-7 receptor α-chain promoter.

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Correspondence to Renata Mazzucchelli.

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Glossary

γδ T cells

T cells that express heterodimers consisting of the γ-chain and δ-chain of the T-cell receptor. They are mainly present in the intestinal epithelium as intraepithelial lymphocytes (IELs). Although the exact function of γδ T cells (or IELs) is still unknown, it has been suggested that mucosal γδ T cells are involved in the innate immune responses of the mucosal immune system.

Natural killer T cells

(NKT cells). T cells that express both natural killer (NK)-cell receptors and an αβ-T-cell receptor (αβ-TCR). In mice, these cells were first identified by their expression of the alloantigen NK1.1 (also known as NKR-P1C). Some NKT cells recognize CD1d-associated lipid antigens and express a restricted repertoire of TCRs. NKT cells are characterized by cytolytic activity and the rapid production of cytokines, including interferon-γ and interleukin-4.

BCL-2-family members

(B-cell-lymphoma-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.

V(D)J recombination

Somatic rearrangement of variable (V), diversity (D) and joining (J) regions of the genes that encode antigen receptors, leading to repertoire diversity of both T-cell and B-cell receptors.

Immature single-positive cells

(ISP cells). Cells at a stage of thymocyte differentiation that occurs between the double-negative (CD4CD8) stage and the double-positive (CD4+CD8+) stage. They are characterized by rapid proliferation and, phenotypically, by the presence of either CD8 (in mice) or CD4 (in humans), with low levels of CD3 expression (in contrast to the more mature single-positive cells, which are CD3hi).

gld mice

These mice have a naturally occurring mutation in CD95 ligand (also known as FAS ligand) that causes a generalized lymphoproliferative disease.

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Mazzucchelli, R., Durum, S. Interleukin-7 receptor expression: intelligent design. Nat Rev Immunol 7, 144–154 (2007). https://doi.org/10.1038/nri2023

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