Regulation of CD4 T cell activation and effector function by inducible costimulator (ICOS)

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Inducible costimulator (ICOS), a member of the CD28 family of costimulatory molecules, is upregulated on the surface of T cells following T cell activation and upon binding to its ligand (ICOSL), initiates a cascade of events that can shape key aspects of the immune response. Although initial studies focused on determining the role of ICOS in Th1 versus T helper 2 (Th2) responses, new insights into its biology have revealed the contribution of ICOS to germinal center formation and isotype switching, as well as its relevance to the fate and function of effector and regulatory CD4+ T cells in the response against self (i.e., tumors) and non-self (i.e., bacterial, worm, and viral infections). This multiplicity of roles positions ICOS at the center of attention for immunotherapy where manipulation of this pathway could lead to novel approaches in the treatment of human diseases.

Introduction

T cell activity is regulated by a complex network of transmembrane receptor/ligand pairs that act in synchrony with the T cell receptor (TCR) to inhibit (coinhibition) or enhance (costimulation) immunity [1]. The CD28 immunoglobulin superfamily includes the coinhibitory molecules PD-1 and CTLA-4 as well as the costimulatory molecules CD28 and inducible costimulator (ICOS, CD278). ICOS was discovered over a decade ago using antibodies raised against activated human T cells and cloned as a 2.6 kb complementary DNA sequence encoding a protein with 39% similarity to human CD28 [2]. For the past several years it has been known that ICOS is upregulated following T cell activation and through interactions with its ligand (ICOSL) on antigen presenting cells (APCs), promotes T cell proliferation and T helper 2 (Th2) differentiation. Recent studies have expanded this view and have demonstrated that, depending on the context of the inflammatory response, ICOS ligation can also promote Th1, Th17, and T follicular helper (Tfh) responses. Current studies have focused on how ICOS costimulates the T cell activity intrinsic to each T cell subset; however, the mechanisms underpinning the contribution of the ICOS pathway to the wide range of T cell responses remain to be studied.

Section snippets

Regulation of ICOS expression

ICOS is expressed at low levels on resting naïve T cells and is rapidly upregulated following TCR ligation and CD28 costimulation [3]. After activation, ICOS is expressed on unpolarized CD4+ T cells, as well as on the Th1, Th2, Th17, Tfh, and Treg lineages [3, 4, 5, 6, 7••].

ICOS expression can be regulated at the transcriptional level by signaling molecules activated downstream of TCR engagement and CD28 costimulation, including the Src kinase Fyn and the MAP kinase ERK [8, 9]. Fyn activates

ICOS is a potent activator of PI3K

ICOS is a disulfide-linked homodimer of 55–60 kDa composed of an extracellular IgV domain, a transmembrane segment, and an intracellular tail containing two tyrosine residues within SH2 binding motifs. Signaling through the ICOS pathway is initiated by interactions with ICOSL (B7h, B7RP-1, CD275) expressed on B cells, macrophages, dendritic cells, and on non-immune cells treated with TNF-α [13, 14]. ICOSL is the only ligand for ICOS, which together with ICOS constitutes a single receptor–ligand

ICOS regulates CD4+ Tfh control of B cell function

ICOS was first identified on the cell surface of germinal center T cells, pointing to its potential role in T cell–B cell interactions [2]. This was confirmed in ICOS knockout mice and common variable immunodeficient (CVID) patients null for ICOS, who have impaired germinal center formation and class switch recombination to IgA, IgE, and certain IgG isotypes [23, 24, 25, 26]. Adoptive transfer experiments directly demonstrated a loss in T cell helper function in ICOS knockout mice [27] whereas

Beyond B cell help: ICOS controls CD4+ effector T cell responses

In addition to Tfh cells, ICOS plays an important role in the development and effector functions of Th1, Th2, Th17, and Treg cells. Early work demonstrated that ICOS costimulates T cell proliferation and promotes secretion of the Th1 and Th2 associated cytokines IFN-γ, TNF-α, IL-4, IL-5, and IL-10 [3, 14, 23, 34]. In vivo, the relevance of ICOS to CD4+ T cell function is further illustrated by ICOS knockout mice, which are incapable of controlling viral or worm infections owing to impaired Th1

Maintenance of memory-effector T cells by ICOS

Although it remains unclear whether ICOS is required for the generation or maintenance of the memory T cell compartment, a role for ICOS in memory CD4+ T cell responses is underscored by ICOS deficient mice, which have a smaller memory T cell compartment as defined by CD44 and CD62L expression [7••, 48]. Although recent work suggests that ICOS deficiency results in a reduced pool of memory T cells owing to a defect in T cell expansion and increased apoptosis [7••], previous work suggested that

Control of immune tolerance by ICOS

In addition to regulating effector T cell function, ICOS is also involved in controlling the regulatory arm of immunity as demonstrated by early work showing that ICOS knockout mice have defects in tolerance induction [44, 50]. In support of this, recent data showing a reduction of CD4+Foxp3+ Tregs in ICOS knockout mice have pinpointed a crucial role for ICOS in maintaining Treg homeostasis [7••, 51]. This reduction could result from a defect in survival and proliferation as signaling through

ICOS as a potential target for immunotherapy?

The role of ICOS in the function of effector T cells has drawn significant attention to this molecule as a potential target for immunotherapy. Of great relevance, in a recent clinical trial where before tumor resection, bladder cancer patients received a blocking anti-CTLA-4 mAb, it was demonstrated that the percentage of ICOShi CD4+ T cells increases in peripheral blood and tumor tissues following treatment with anti-CTLA-4 mAbs [55•, 56]. Upon restimulation, ICOShi CD4+ T cells produce

Conclusions

ICOS expression is upregulated following initial T cell activation, and upon engagement of its ligand, ICOS influences T cell activity. In the early stages of T cell priming, ICOS can promote Th2 differentiation through upregulation of Th2 transcription factors. However, in differentiated CD4+ T cells, ICOS can promote T cell responses intrinsic to each subset, such as IFN-γ and IL-4 secretion by Th1 and Th2 cells, respectively (Figure 1). Overall, ICOS plays an essential role in the function

References and recommended reading

Papers of particular interest, published within the annual period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We would like to thank Tsvetelina P. Hoang, Xingxing Zang, and Alejandro Sepulveda for critical review of this manuscript. Tyler R. Simpson is supported by a Canadian Institutes of Health Doctoral Research Award. Sergio A. Quezada is a Research Fellow funded by the Irvington Institute Fellowship Program of the Cancer Research Institute, USA, and a junior member of the Millennium Nucleus on Immunology and Immunotherapy, Pontifícia Universidad Católica de Chile. James P. Allison is an

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