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. Author manuscript; available in PMC: 2016 Oct 25.
Published in final edited form as: Nat Rev Immunol. 2015 Nov 16;15(12):771–783. doi: 10.1038/nri3919

Figure 1. Models contrasting IL-15 and IL-2 signalling and the regulation of naive versus tissue-resident effector memory T cells.

Figure 1

a | Interleukin-15 (IL-15) signalling compared with IL-2 signalling. The main mechanism by which IL-15 interacts with its receptor in vivo is trans-presentation. IL-15 is assembled as an IL-15–IL-15 receptor α-subunit (IL-15Rα) complex intracellularly in the endoplasmic reticulum (ER), then shuttled to the cell surface and presented by distressed cells in trans to responder cells expressing a heterodimer of the IL-2/IL-15 receptor β-chain (IL-2/IL-15Rβ) and the common cytokine receptor γ-chain (γc). This receptor is constitutively expressed by effector and memory T cells, as well as by natural killer (NK) cells. Unlike IL-15, IL-2 is mainly secreted as a soluble factor by T cells in response to co-stimulation. IL-2 can bind the IL-2/IL-15Rβ–γc receptor with low affinity and interacts with high affinity in an autocrine manner with the trimeric receptor IL-2Rα–IL-2/IL-15Rβ–γc. This trimeric receptor is only transiently expressed on all activated T cells and NK cells. b | Regulation of naive versus effector cytotoxic T lymphocytes (CTLs). Naive or memory CD8+ T cells require, in addition to T cell receptor (TCR) signals (signal 1), co-stimulation (signal 2) provided by CD28 and CD40 ligand (CD40L) — which recognize B7 and CD40, respectively, expressed by dendritic cells — to become activated and undergo differentiation. In the absence of co-stimulation, very little IL-2 is produced by T cells, and cells that receive a TCR signal die or become anergic. IL-2, which is induced in response to signal 2, promotes T cell proliferation and prevents anergy159, and it therefore functions as a co-signal. By contrast, tissue-resident effector memory CD8+ T cells classically do not express CD28 and do not require signal 2 for survival. Furthermore, tissue cells do not express B7. However, we propose that a different form of co-stimulation is required for tissue effector CTLs to exert their effector function: signal 2 and co-signal 2 are provided by activating NK receptors recognizing non-classical MHC class I molecules and by IL-15, respectively, that are induced on tissue cells under conditions of stress and infection.