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Co-stimulatory members of the TNFR family: keys to effective T-cell immunity?

Nature Reviews Immunology volume 3, pages 609–620 (2003)Cite this article

Key Points

  • Five interactions between the tumour-necrosis factor receptor (TNFR)–TNF family members have emerged as positive regulators of T cells: OX40–OX40 ligand (OX40L), 4-1BB–4-1BBL, CD27–CD70, herpes-virus entry mediator (HVEM)–LIGHT and CD30–CD30L. The co-stimulatory TNFR-family members are mainly expressed by T cells and their ligands by antigen-presenting cells (APCs).

  • There are two patterns of expression of the co-stimulatory TNFR-family molecules: constitutive (such as CD27 and HVEM) and inducible (such as OX40, 4-1BB and CD30). All can potentially participate in T-cell responses either at the time of T-cell activation or within the first few days of activation.

  • In vitro and in vivo data indicate that HVEM–LIGHT interactions promote the early activation and clonal expansion of T cells, CD27–CD70 might also help to maintain early proliferation, OX40–OX40L and 4-1BB–4-1BBL and CD30–CD30L seem to regulate later expansion of T-cell numbers at the peak of the response.

  • Co-stimulatory TNFR-family signalling seems to regulate T-cell division, survival and effector function by activating nuclear factor-κB (NF-κB), JNK pathways and phosphatidylinositol 3-kinase (PI3K)–protein kinase B (PKB) pathways.

  • It is not clear whether all the TNFR-family molecules are required to function together (simultaneously or sequentially) to regulate a response or whether different responses require different co-stimulatory interactions.

  • Survival signals from TNFR-family members might be crucial for secondary responses and the maintenance of T-cell memory.

  • Blocking co-stimulatory TNF family members might be of benefit in inflammatory and autoimmune diseases and in preventing transplant rejection, whereas promoting these interactions might enhance antitumour immunity.

Abstract

Interactions between co-stimulatory ligands and their receptors are crucial for the activation of T cells, the prevention of tolerance and the development of T-cell immunity. It is now evident that members of the immunoglobulin-like CD28–B7 co-stimulatory family cannot fully account for an effective long-lasting T-cell response or the generation of memory T cells. Several members of the tumour-necrosis factor receptor (TNFR) superfamily — OX40, 4-1BB, CD27, CD30 and HVEM (herpes-virus entry mediator) — are poised to deliver co-stimulatory signals both early and late after encounter with antigen. The roles of these molecules in initiating and sustaining the T-cell response and in promoting long-lived immunity are discussed.

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Figure 1: Structural organization of the co-stimulatory TNFR–TNF-family members.
Figure 2: Generalized time course of expression of co-stimulatory TNFR-family members.
Figure 3: Signalling intermediates in TNFR-family co-stimulation.
Figure 4: Hypothetical model of TNFR control of primary T-cell responses.
Figure 5: Control of antigen-specific T-cell numbers by TNFR-family co-signals.

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Authors and Affiliations

  1. Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, California, 92121, San Diego, USA

    Michael Croft

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DATABASES

LocusLink

4-1BB

4-1BBL

BCL2

BCL-XL

BFL1

CD27

CD28

CD30

CD30L

CD70

CD80

CD86

HVEM

ICOS

IFN-γ

LIGHT

LTα3

LTβR

NF-κB

OX40

OX40L

PI3K

PKB

TRAF1

TRAF2

TRAF3

TRAF5

Entrez

LCMV

VSV

Glossary

MIXED-LYMPHOCYTE REACTION

(MLR). A proliferative and cytokine response that is brought about when T cells from one donor respond to antigen-presenting cells from a second donor. In most cases, this is an allogeneic reaction that involves the recognition of mismatched peptide–MHC molecules.

T HELPER 1/T HELPER 2 CELLS

(TH1/TH2). Distinct subsets of activated CD4+ T cells. TH1 cells produce interferon-γ, lymphotoxin and tumour-necrosis factor, and support cell-mediated immunity. TH2 cells produce interleukin-4 (IL-4), IL-5, IL-9 and IL-13, and support humoral immunity.

TYPE 1/2 CYTOTOXIC T CELLS (TC1/TC2).

A designation that is used to describe subsets of CD8+ cytotoxic T lymphocytes. TC1 cells typically secrete interferon-γ and tumour-necrosis factor and have marked cytotoxic capacity, whereas TC2 cells secrete interleukin-4 (IL-4), IL-5 and IL-10, and are less effective killers.

NUCLEAR FACTOR-κB

(NF-κB). A family of transcription factors that are important for pro-inflammatory and anti-apoptotic responses. They are activated by the phosphorylation and subsequent ubiquitin-dependent proteolytic degradation of their respective inhibitors, known as inhibitor of NF-κB (IκB). Phosphorylation of IκB occurs through tissue-specific kinases, IκB kinase 1 (IKK1) and IKK2.

JUN N-TERMINAL KINASE

(JNK). A mitogen-activated protein (MAP) kinase that phosphorylates JUN and other components of the AP1 (FOS–JUN) group of transcription factors. This pathway has been implicated in promoting cytokine expression and proliferation, and in some cases might regulate apoptosis.

PROTEIN KINASE B

(PKB). A serine/threonine kinase that is phosphorylated and activated by phosphatidylinositol 3-kinase (PI3K), and can regulate cell division and cell survival through actions on cell-cycle inhibitors and both pro- and anti-apoptotic members of the BCL2 family.

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Croft, M. Co-stimulatory members of the TNFR family: keys to effective T-cell immunity?. Nat Rev Immunol 3, 609–620 (2003). https://doi.org/10.1038/nri1148

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