Elsevier

Molecular Immunology

Volume 117, January 2020, Pages 180-188
Molecular Immunology

Control of memory CD8+ T cell longevity and effector functions by IL-15

https://doi.org/10.1016/j.molimm.2019.11.011Get rights and content

Highlights

  • IL-15 functions as both a homeostatic and as an inflammatory cytokine.

  • IL-15 controls homeostatic proliferation and survival of memory CD8+ T cells.

  • Many effector functions (e.g. cytotoxicity, trafficking) of memory CD8 + T cells are regulated by IL-15.

Abstract

IL-15 is a member of the common gamma chain family of cytokines and plays important roles in regulating several aspects of innate and adaptive immunity. Besides its established role in controlling homeostatic proliferation and survival of memory CD8+ T cells and natural killer cells, recent findings demonstrate that inflammatory IL-15 can also stimulate a variety of effector functions, such as enhanced cytotoxicity, entry into the cell cycle, and trafficking into non-lymphoid tissues. Here, we discuss how IL-15 is critical in regulating many functions of memory CD8+ T cells and how these processes act collectively to ensure optimal protective cellular immunity against re-infections.

Introduction

Cytotoxic CD8+ T cells provide host defense and protective immunity by directly engaging and eliminating cells infected with viruses and other intracellular pathogens. After their selection and maturation in the thymus, antigen-naïve CD8+ T cells enter the periphery and begin surveying secondary lymphoid organs for “non-self” peptides presented by MHC-I that will activate their individual, uniquely expressed T cell receptor (TCR). Following activation, CD8+ T cells undergo massive proliferative expansion and differentiate into effector cells that are able to infiltrate non-lymphoid tissues and produce cytokines including IFNγ and TNFα. This transient expansion phase is followed by rapid contraction of the antigen-specific T cell population, where the majority of the clonally expanded effector CD8+ T cells die via apoptosis. Effector CD8+ T cells that survive contraction then transition into long-lived memory cells that can provide enhanced protective immunity against re-infection (Harty and Badovinac, 2008).

Besides the overall numerical increase of the antigen-specific T cell population, several other functional properties of memory CD8+ T cells distinguishes them from naïve T cells (Jameson and Masopust, 2018). For instance, memory CD8+ T cells produce cytokines and execute cytolysis immediately following antigen recognition. Memory CD8+ T cells also undergo low levels of basal proliferation, survive independently of any additional TCR-stimulation, and are more broadly distributed compared to naïve T cells; able to traffic into and also become seeded within many non-lymphoid tissues. Thus, memory CD8+ T cells possess a number of specialized properties that ensure both extended longevity and the capacity to rapidly respond to re-invasion of pathogens and nearly all of these specialized functions of memory CD8+ T cells are/can be regulated by interleukin-15 (IL-15).

IL-15 belongs to a family of cytokines that utilize the IL-2 receptor gamma chain (CD132; common gamma chain; γc) for signal transduction, which also includes IL-2, IL-4, IL-9, and IL-21 (Lin and Leonard, 2018). Despite sharing this critical signaling molecule, the downstream transcriptional targets and subsequent biological consequences of each of these cytokines varies considerably. One unique feature of IL-15 is that it functions as both a homeostatic cytokine (active during steady-state, non-inflammatory conditions), but also as an inflammatory cytokine, as levels of IL-15 detected in the circulation increase significantly following infections or various forms of inflammatory challenges. Although originally identified as a factor critical for controlling the homeostatic proliferation and survival of memory CD8+ T cells and natural killer (NK) cells (Kennedy et al., 2000), more recent findings have highlighted major roles for IL-15 in regulating a variety of additional specialized effector functions of memory CD8+ T cells (Fig. 1). Here, we discuss the mechanisms that control IL-15 signaling in vivo, how IL-15 contributes to the homeostatic proliferation and survival of memory CD8+ T cells, and finally, recent studies that have identified IL-15 as a critical factor that controls a variety of effector functions that collectively optimize the memory CD8+ T cell response against re-infections.

Section snippets

IL-15 and IL-15 receptor signaling

IL-15 and IL-2 both signal through a shared receptor complex consisting of the IL-2/15Rβ chain (CD122) and the γc. Upon activation, most T cells will express IL-2Rα (CD25), resulting in a cell surface heterotrimeric IL-2 receptor complex that exhibits high affinity for IL-2 (Fig. 2A, left). Similarly, IL-15 also signals through a heterotrimeric receptor, consisting of the shared subunits (CD122 and the γc) and the unique high affinity receptor, IL-15Rα (CD215). (Giri et al., 1995a, b; Grabstein

IL-15 regulates homeostatic proliferation and survival of memory CD8+ T cells

One classic feature of memory CD8+ T cells is their low level of basal proliferation that occurs in vivo independent of any new antigen encounter, a process often referred to as homeostatic proliferation. IL-15 is the primary driver of memory CD8+ T cell homeostatic proliferation and extended BrdU incorporation analyses in mice suggest a “doubling-rate” of approximately nine weeks (Parretta et al., 2008), which is estimated to result in the complete renewal of the memory CD8+ T cell population

Regulation of memory CD8+ T cell effector functions by IL-15

While the role of IL-15 in regulating memory CD8+ T cell longevity during homeostasis has long been appreciated, several recent studies have begun to highlight an important role for IL-15 that is induced during inflammatory conditions. In fact, IL-15 can impact several features of memory CD8+ T cells that confer them a functional advantage compared to naïve CD8+ T cells, including the exhibition of effector functions, priming proliferation and promoting trafficking into non-lymphoid tissues.

Concluding remarks and perspectives

Here, we discussed a variety of mechanisms by which IL-15 controls multiple fundamental features of memory CD8+ T cell biology, but many open questions still remain. As described, trans-presentation seems to be the primary mechanism that delivers IL-15 to memory CD8+ T cells during steady state conditions to promote homeostatic proliferation, but how IL-15 signals to memory CD8+ T cells during infection and a complete characterization of transcriptional targets remains relatively ill-defined.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

The authors would like to thank the members of the Nolz and Richer labs for helpful discussions and Dr. Stephanie A. Condotta for generating figures and critical reading of the manuscript. Research in the Nolz lab is supported by the National Institutes of Health (R01-AI132404). Research in the Richer Lab is supported by the Canadian Institutes of Health Research (PJT-152903, PJT-162212); the Natural Sciences and Engineering Research Council of Canada (RGPIN-2016-04713); and the Canada

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