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IL-15 functions as a danger signal to regulate tissue-resident T cells and tissue destruction

Nature Reviews Immunology volume 15, pages 771–783 (2015)Cite this article

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Abstract

In this Opinion article, we discuss the function of tissues as a crucial checkpoint for the regulation of effector T cell responses, and the notion that interleukin-15 (IL-15) functions as a danger molecule that communicates to the immune system that the tissue is under attack and poises it to mediate tissue destruction. More specifically, we propose that expression of IL-15 in tissues promotes T helper 1 cell-mediated immunity and provides co-stimulatory signals to effector cytotoxic T cells to exert their effector functions and drive tissue destruction. Therefore, we think that IL-15 contributes to tissue protection by promoting the elimination of infected cells but that when its expression is chronically dysregulated, it can promote the development of complex T cell-mediated disorders associated with tissue destruction, such as coeliac disease and type 1 diabetes.

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Figure 1: Models contrasting IL-15 and IL-2 signalling and the regulation of naive versus tissue-resident effector memory T cells.
Figure 2: IL-15 has pleiotropic effects on tissue-resident cells that promote TH1 cell-mediated responses and tissue destruction.
Figure 3: IL-15, NKG2D and the TCR function in synergy to enable CTLs to kill distressed target cells.
Figure 4: Proposed roles of IL-15 in tissue protection and tissue destruction.
Figure 5: Lack of IL-15 expression by tissue cells is associated with latent autoimmunity.

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Acknowledgements

The authors thank patients with coeliac disease and their family members, as well as the University of Chicago Coeliac Disease Center, for supporting their research. The authors also thank L.B. Barreiro and B. Sally for critical reading of the manuscript. The work was supported by grants from the Digestive Diseases Research Core Center (DK42086) at the University of Chicago, from the US National Institutes of Health (R01DK67180 and R01DK098435) to B.J. and from the SickKids Foundation (NI15-040) to V.A.

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  1. Bana Jabri is at the Departments of Medicine, Pathology and Pediatrics, University of Chicago, Knapp Center for Biomedical Discovery (KCBD), Chicago, Illinois 60637, USA.,

    Bana Jabri

  2. Valérie Abadie is at the Department of Microbiology, Infectious Diseases, and Immunology, University of Montreal, and the Centre Hospitalier Universitaire (CHU) Sainte-Justine Research Center, Montreal, Quebec H3T 1C5, Canada.,

    Valérie Abadie

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Glossary

Activation-induced cell death

(AICD). A phenomenon in T cells, in which activation through the T cell receptor results in apoptosis. CD95 (also known as Fas) and its ligand (CD95L) are the main regulators of AICD, and the engagement of CD95 ultimately leads to DNA cleavage by caspase-activated DNase (CAD).

Latent autoimmune diabetes in adults

(LADA). A disorder characterized by the presence of diabetes-associated autoantibodies and islet-reactive T cells in the absence of β-cell destruction and overt diabetes.

Lymphokine-activated killer activity

(LAK activity). The ability of T cells to lyse target cells in the absence of specific antigenic stimuli and MHC restriction. LAK cells can be generated in vitro in the presence of interleukin-15 (IL-15) or high concentrations of IL-2.

Potential coeliac disease

A form of coeliac disease defined by the presence of transglutaminase- and gluten-specific antibodies and compatible HLA molecules in the absence of villous atrophy.

Tissue-resident effector memory T cells

(TRM cells). A population of non-circulating memory T cells with an effector-like phenotype that have entered tissues during the effector phase of immune responses and can permanently reside in tissues.

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Jabri, B., Abadie, V. IL-15 functions as a danger signal to regulate tissue-resident T cells and tissue destruction. Nat Rev Immunol 15, 771–783 (2015). https://doi.org/10.1038/nri3919

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