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

  title={Co-stimulatory members of the TNFR family: keys to effective T-cell immunity?},
  author={Michael Croft},
  journal={Nature Reviews Immunology},
  • M. Croft
  • Published 1 August 2003
  • Biology, Medicine
  • Nature Reviews Immunology
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… 

TNF/TNFR family members in costimulation of T cell responses.

  • T. Watts
  • Medicine, Biology
    Annual review of immunology
  • 2005
This review focuses on CD27, 4-1BB, OX40, HVEM, CD30, and GITR, all of which can have costimulatory effects on T cells, and shows promise for several therapeutic applications, including cancer, infectious disease, transplantation, and autoimmunity.

The role of TNF superfamily members in T-cell function and diseases

  • M. Croft
  • Biology, Medicine
    Nature Reviews Immunology
  • 2009
The biology of four different ligand–receptor interactions and how blocking or inducing the signalling pathways that are triggered by these different interactions can be an effective way to modulate immune responses are explored.

Importance of reverse signaling of the TNF superfamily in immune regulation

TNF-related ligands (with the exception of lymphotoxin-α) are synthesized as type II transmembrane proteins, though many of them also have soluble forms. An increasing number of publications report

The evolving crosstalk between co-stimulatory and co-inhibitory receptors: HVEM-BTLA.

The role of OX40-mediated co-stimulation in T-cell activation and survival.

OX40 ligation has been shown to augment CD4 and CD8 T-cell clonal expansion, effector differentiation, survival, and in some cases, abrogate the suppressive activity of regulatory FoxP3+CD25+CD4+ T cells.

The role of ICOS and other costimulatory molecules in allergy and asthma

The role of costimulatory signals, which include CTLA-4, PD-1 and the recently described Ig superfamily members BTLA and TIM-3, in the pathogenesis of asthma and allergic responses is discussed.

The TNF family in T cell differentiation and function--unanswered questions and future directions.

  • M. Croft
  • Biology, Medicine
    Seminars in immunology
  • 2014

Costimulation: critical pathways in the immunologic regulation of asthma

The fundamental properties of costimulatory molecules are described, including cytotoxic T lymphocyte-associated antigen (CTLA)-4, programmed death (PD)-1, and B and T lymphocytes attenuator (BTLA), which dampen immune responses are addressed.

The role of the T-cell costimulatory molecule Tim-1 in the immune response

A reasonable approach toward gaining novel insights into immunity and allergic disease is to define the mechanisms that control Th2 cell differentiation and mature Th1 cell function.



Modulation of T-cell-mediated immunity in tumor and graft-versus-host disease models through the LIGHT co-stimulatory pathway

These studies identify a previously unknown T-cell co-stimulatory pathway as a potential therapeutic target and isolate a mouse homolog of human LIGHT, a member of the tumor necrosis factor (TNF) ‘superfamily’.

CD27 is required for generation and long-term maintenance of T cell immunity

It is found that CD27 makes essential contributions to mature CD4+ and CD8+ T cell function: CD27 supported antigen-specific expansion of naïve T cells, independent of the cell cycle–promoting activities of CD28 and interleukin 2.

LIGHT, a TNF-Like Molecule, Costimulates T Cell Proliferation and Is Required for Dendritic Cell-Mediated Allogeneic T Cell Response1

It is demonstrated that LIGHT is selectively expressed on immature dendritic cells (DCs) generated from human PBMCs, and engagement of LIGHT costimulates human T cell proliferation, amplifies the NF-κB signaling pathway, and preferentially induces the production of IFN-γ, but not IL-4, in the presence of an antigenic signal.

Characterization of the human CD27 ligand, a novel member of the TNF gene family.

CD27 and its ligand are identified as potentially important structures involved in cellular interactions between T and B lymphocytes and exerted a potent inhibitory effect on the proliferation of T cells in response to allogeneic B cells and PHA.

Engagement of CD27 with its ligand CD70 provides a second signal for T cell activation.

It is demonstrated here that interaction of CD27 with its ligand provides a potent second signal for cytokine production, induction of activation Ags, and proliferation of unprimed CD45RA+, and to a lesser extent, of primed CD45R0+ peripheral blood T cells.

4-1BB ligand, a member of the TNF family, is important for the generation of antiviral CD8 T cell responses.

It is indicated that T cells have distinct costimulatory requirements: optimal CD8 responses require 4-1BBL-dependent interactions, whereas CD4 responses are minimally affected by4-1BB costimulation, but require CD40-CD40L and B7- dependent interactions.

Antibodies to TR2 (herpesvirus entry mediator), a new member of the TNF receptor superfamily, block T cell proliferation, expression of activation markers, and production of cytokines.

Results suggest that TR2 is involved in the activation cascade of T cell responses and TR2 mAbs prevent optimal T cell proliferation, cytokine production, and expression of activation markers.

Danger and OX40 Receptor Signaling Synergize to Enhance Memory T Cell Survival by Inhibiting Peripheral Deletion1

A cell surface receptor (OX40) expressed on effector CD4 T cells, which when engaged in conjunction with a danger signal, rescues Ag-stimulated effector cells from activation-induced cell death in vivo is defined, providing a potential target to limit the number of auto-Ag-specific memory T cells in autoimmune disease.

A TNF Family Member LIGHT Transduces Costimulatory Signals into Human T Cells1

It is demonstrated that TR6 bound to both Th1 and Th2 cells, according to flow cytometry, and that the association was inhibited by soluble LIGHT, suggesting that TR 6 delivers costimulation through its ligand(s) on the T cell surface, and at least the major part of such costimulating is via LIGHT.