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Co-stimulation and T cells as therapeutic targets

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Full activation and differentiation of resting T cells into effector T cells requires at least two signals, the first through engagement of the T cell antigen receptor (TCR) by the antigen-major histocompatibility complex (MHC) on antigen-presenting cells (APCs), and the second by engagement of co-stimulatory molecules such as CD28, on T cells by ligands such as CD80/86 on APCs. Effector T cell differentiation is associated with proliferation, secretion of cytokines and expression of additional surface molecules. These inducible structures may have stimulatory (ICOS, OX40 and 4-1BB) or inhibitory (cytotoxic T-lymphocyte antigen (CTLA)-4) potential. To the extent that T cells have a role in particular immune-mediated diseases, interruption of T cell co-stimulation is a potentially worthwhile approach to the treatment of those conditions. This article summarises the experience in treating rheumatological disease by perturbation of T cell co-stimulation, and also describes structures that could be future targets for this type of therapeutic approach.

Section snippets

CD28:cytotoxic T-lymphocyte antigen (CTLA)-4 (CD152)/CD80:CD86

CD28 is the prototypic T cell receptor for co-stimulatory signals. CTLA-4, which is up-regulated on activated T cells, also binds to the CD28 ligands CD80/86 (B7.1 and B7.2), and this interaction inhibits further T cell activation [1], [2], [3], [4].

The ligation of CD28 by CD80/86 not only sends co-stimulatory signals into the T cell but can also send activating signals into the antigen-presenting cells (APCs) [5]. Maturation and activation of APCs are accompanied by expression of other

Clinical studies of abatacept in RA

After a successful Phase I study in which 50% of the patients achieved American College of Rheumatology (ACR) 20 responses without any significant adverse events, a phase II study was done in patients with active disease despite standard doses of methotrexate. In this study, abatacept was administered concurrently with stable doses of methotrexate for 6 months. The ACR20/50/70 responses were 60%, 36% and 16% in the group receiving abatacept plus methotrexate compared with 25%, 12% and 2% in the

Belatacept –A modified abatacept

Belatacept, the second-generation modified version of abatacept, is composed of an altered extracellular domain of CTLA-4 fused to an altered Fc portion of human IgG. The Fc portion contains two mutations that reduce its ability to bind to Fc receptors. The CTLA-4 component of belatacept bears two mutations that increase binding affinity to CD80 and CD86. Belatacept binds to both CD80 and CD86, but with a greater affinity for CD80. However, the binding to both CD80 and CD86 on APCs is required

OX40 (CD134)/OX40L (CD252)

OX40 is predominantly expressed on activated CD4 and CD8 T cells, following stimulation via T-cell receptor (TCR) and CD28, and its ligand. OX40L is expressed on dendritic cells, B cells, macrophages and endothelial cells [28]. Pro-inflammatory cytokines IL-1, IL-2 and TNF can further augment the expression of OX40. OX40L is induced on APCs after stimulation via Toll like receptors as well as CD40 [29], [30]. There is bidirectional activation of T cells and APCs via the OX40–OX40L pathway.

ICOS (CD278)/ICOSL (CD275)

ICOS/ICOSL belongs to the CD28 family of co-stimulatory molecules. ICOS is predominantly expressed on CD4 and CD8 T cells following activation by CD28. ICOSL is predominantly expressed on B cells. Studies in mice as well as in humans have shown that ICOS signalling into the T cells induces IL-4 and IL-10 secretion from T cells.

ICOS-deficient mice have attenuated IgM and IgG responses, as well as reduced levels of the inflammatory cytokine IL-17, and are resistant to inflammatory arthritis,

4-1BB (CD137)/4-1BBL(CD137L)

4-1BB is induced on CD4 and CD8 T cells following stimulation via TCR and CD28. The ligand for 4-1BB, 4-1BBL is expressed on activated B cells, dendritic cells and macrophages. In addition, under certain circumstances dendritic cells express 4-1BB and T cells express the 4-1BBL [44].

The functional consequences of ligation of this pair are complex. The duration of expression of these molecules can be transient or sustained, depending on the cell type and the immune microenvironment. The effects

CD4 (OKT4, Leu 3a and T4)

CD4 is a type I transmembrane glycoprotein and a member of the Ig superfamily. It is a co-receptor in major histocompatibility complex (MHC) class II antigen-restricted T-cell activation, involved in stabilising the MHC/TCR complex [49]. In addition to MHC class II, ligands for CD4 include the viral gp120 protein of HIV retroviruses, IL-16 and gp17. CD4 is also involved in regulation of T–B lymphocyte adhesion in the absence of antigen recognition [50]. CD4 is a receptor for IL-16 and binding

CD5/CD72 (Tp67, T1, Ly1 and Leu-1)

CD5 is a type I transmembrane glycoprotein expressed by most T cells and some B cells. The putative ligand of CD5 in humans is CD72. CD5 can transmit both inhibitory and stimulatory signals depending on the cell type and its maturation stage [49]. CD5 transmits inhibitory signals in thymocytes and B1a cells but is a co-stimulatory signal receptor on mature peripheral T cells [49]. Expression of CD5 regulates responsiveness of human T cells to IL-1 [50]. The B1a CD5-positive population is

CD40–CD40ligand (Bp50 and TNF receptor 5)–ligand CD154 (CD40L)

CD40 is a type I integral membrane glycoprotein that is expressed on APCs and is the receptor for CD40L expressed on activated CD4 T cells, CD8 T cells, mast cells, natural killer (NK) cells, monocytes and activated platelets. Binding of CD40L provides a co-stimulatory signal to B cells, promoting growth, differentiation and isotype switching [49]. Binding of CD40L by CD40 transmits activating signals to T cells and APCs to express B7 molecules, which in turn stimulates further T-cell

LFA-3 (CD58)/CD2

Leucocyte function-associated antigen (LFA)-3 is a member of the CD2 family within the Ig superfamily that occurs as a glycophosphatidylinositol-anchored and type I integral membrane protein [49]. LFA-3 is the ligand for CD2 and mediates adhesion between killer and target cells and in cell-mediated cytotoxicity. Adhesion through CD2 occurs between APCs and T lymphocytes, thymocytes and thymic epithelial cells and T lymphocytes and erythrocytes.

Alefacept is a dimeric fusion protein consisting of

CD11a/CD18

CD11a is a type I integral membrane glycoprotein and a member of the integrin α-chain family. CD11a complexes with CD18 to form LFA-1. Ligands for LFA-1 are CD54 (inter-cellular adhesion molecule (ICAM)-1), CD102 (ICAM-2), CD50 (ICAM-3), ICAM-4, ICAM-5 and JAM-1 (CD321). LFA-1 is an important adhesion and signal transduction molecule involved in inflammation [49].

Efalizumab is a recombinant humanised IgG1 monoclonal antibody that binds to CD11a, the α-subunit of LFA-1. LFA-1 binds to ICAM-1,

CD49d (Integrin alpha-4-chain and very late antigen (VLA)-4-alpha chain)

CD49d is a type I transmembrane glycoprotein which non-covalently associates with CD29 molecules to form VLA-4 (integrin α4/β1) and with the β7 integrin subunit to form the α4/β7 integrin. CD49d regulates multiple inflammatory responses by enhancing adhesion to and rolling of lymphocytes on vascular endothelium by binding to vascular cellular adhesion molecule (VCAM)-1, allowing lymphocyte migration from circulation into tissue [49]. CD49d, when associated with β7 integrin, is involved in the

CD97/CD55/chondroitin sulphate

CD97 is a transmembrane protein belonging to the secretin receptor superfamily, G-protein-coupled receptor family and the epidermal growth factor-seven-span transmembrane family (EGF-TM7) of molecules. CD97 is expressed on activated T and B cells and constitutively by monocytes, macrophages, dendritic cells and granulocytes. CD97 binds CD55 and chondroitin sulphate [49]. EGF domains mediate CD97 interactions with different ligands, with CD55 interacting with EGF domains 1 and 2, and chondroitin

CD52

CD52, a highly N-glycosylated protein, C-terminally anchored in the membrane via glycophosphatidylinositol, is highly expressed on the surface of thymocytes, CD4 and CD8 lymphocytes, B lymphocytes, monocytes, macrophages, NK cells, dendritic cells and eosinophils [49]. Alemtuzumab (Campath-1H) is a humanised IgG1 kappa monoclonal antibody to CD52 and is Administration FDA approved for the treatment of B-cell chronic lymphocytic leukaemia. In 2005, the FDA issued an alert as three patients in a

CD27/CD70 (CD27 ligand)

CD70 is a type II transmembrane glycoprotein member of the TNF superfamily. CD70 is expressed on activated B cells, T cells, NK cells and dendritic cells. CD70 binds CD27, which is constitutively expressed on resting T cells and is further up-regulated upon T cell activation. CD70–CD27 plays an important role in T-cell priming by inducing proliferation of co-stimulated T cells, enhancing the generation of cytolytic and memory T cells.

Increased numbers of circulating CD70-positive CD4 T cells

Conclusion

Inhibition of T cell co-stimulation is a promising but complex approach to the treatment of immune-mediated diseases. Many of the co-stimulatory molecules discussed are not specific for T cells and are expressed on other cell lineages. For this reason, interference with these molecules could lead to off-target effects, such as induction of thrombo-embolic events in SLE patients by anti-CD40L due to CD40L expression on platelets. Multiple arms of host–defence mechanisms are required to combat

Conflict of interest

The authors have no financial or personal relationships with other people or organisations that could inappropriately influence the content of this article.

Acknowledgements

Thanks to Judith Endres for review of the article and Donna Cash for article preparation and to Sagar Patel for his artistic contributions. Supported by grants from the NIH (NIAMS AR38477), NIAMS AR54323, Arthritis National Research Foundation and the ACR Research and Education Foundation.

References (79)

  • M.F. Krummel et al.

    CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation

    J Exp Med

    (1995)
  • C.A. London et al.

    Functional responses and costimulator dependence of memory CD4 + T cells

    J Immunol

    (2000)
  • M.P. Ndejembi et al.

    Control of memory CD4 T cell recall by the CD28/B7 costimulatory pathway

    J Immunol

    (2006)
  • G. Suntharalingam et al.

    Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412

    N Engl J Med

    (2006)
  • L.M. Webb et al.

    Prevention and amelioration of collagen-induced arthritis by blockade of the CD28 co-stimulatory pathway: requirement for both B7-1 and B7-2

    Eur J Immunol

    (1996)
  • L.W. Moreland et al.

    Costimulatory blockade in patients with rheumatoid arthritis: a pilot, dose-finding, double-blind, placebo-controlled clinical trial evaluating CTLA-4Ig and LEA29Y eighty-five days after the first infusion

    Arthritis Rheum

    (2002)
  • J.M. Kremer et al.

    Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig

    N Engl J Med

    (2003)
  • J.M. Kremer et al.

    Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: twelve-month results of a phase iib, double-blind, randomized, placebo-controlled trial

    Arthritis Rheum

    (2005)
  • R. Westhovens et al.

    Safety and efficacy of the selective costimulation modulator abatacept in patients with rheumatoid arthritis receiving background methotrexate: a 5-year extended phase IIB study

    J Rheumatol

    (2009)
  • M.C. Genovese et al.

    Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition

    N Engl J Med

    (2005)
  • M.C. Genovese et al.

    Efficacy and safety of the selective co-stimulation modulator abatacept following 2 years of treatment in patients with rheumatoid arthritis and an inadequate response to anti-tumour necrosis factor therapy

    Ann Rheum Dis

    (2008)
  • M. Schiff et al.

    Efficacy and safety of abatacept or infliximab vs placebo in ATTEST: a phase III, multi-centre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate

    Ann Rheum Dis

    (2008)
  • J.M. Kremer et al.

    Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: a randomized trial

    Ann Intern Med

    (2006)
  • R. Westhovens et al.

    Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors

    Ann Rheum Dis

    (2009)
  • M. Weinblatt et al.

    Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antirheumatic drugs: A one-year randomized, placebo-controlled study

    Arthritis Rheum

    (2006)
  • M. Weinblatt et al.

    Selective costimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept: a randomised clinical trial

    Ann Rheum Dis

    (2007)
  • M.H. Weisman et al.

    Reduction of inflammatory biomarker response by abatacept in treatment of rheumatoid arthritis

    J Rheumatol

    (2006)
  • M.H. Buch et al.

    Mode of action of abatacept in rheumatoid arthritis patients having failed tumour necrosis factor blockade: a histological, gene expression and dynamic magnetic resonance imaging pilot study

    Ann Rheum Dis

    (2009)
  • R. Latek et al.

    Assessment of belatacept-mediated costimulation blockade through evaluation of CD80/86-receptor saturation

    Transplantation

    (2009)
  • F. Vincenti et al.

    Costimulation blockade with belatacept in renal transplantation

    N Engl J Med

    (2005)
  • L.S. Walker et al.

    Compromised OX40 function in CD28-deficient mice is linked with failure to develop CXC chemokine receptor 5-positive CD4 cells and germinal centers

    J Exp Med

    (1999)
  • Y. Ohshima et al.

    Expression and function of OX40 ligand on human dendritic cells

    J Immunol

    (1997)
  • K. Murata et al.

    Impairment of antigen-presenting cell function in mice lacking expression of OX40 ligand

    J Exp Med

    (2000)
  • S. Saijo et al.

    Suppression of auto-immune arthritis in interleukin-1-deficient mice in which T cell activation is impaired due to low levels of CD40 ligand and OX40 expression on T cells

    Arthritis Rheum

    (2002)
  • T. Yoshioka et al.

    Contribution of OX40/OX40 ligand interaction to the pathogenesis of rheumatoid arthritis

    Eur J Immunol

    (2000)
  • E.P. Boot et al.

    CD134 as target for specific drug delivery to auto-aggressive CD4 + T cells in adjuvant arthritis

    Arthritis Res Ther

    (2005)
  • D. Brugnoni et al.

    CD134/OX40 expression by synovial fluid CD4 + T lymphocytes in chronic synovitis

    Br J Rheumatol

    (1998)
  • R. Giacomelli et al.

    T lymphocytes in the synovial fluid of patients with active rheumatoid arthritis display CD134-OX40 surface antigen

    Clin Exp Rheumatol

    (2001)
  • A. Passacantando et al.

    Synovial fluid OX40T lymphocytes of patients with rheumatoid arthritis display a Th2/Th0 polarization

    Int J Immunopathol Pharmacol

    (2006)
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