3Co-stimulation and T cells as therapeutic targets
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)
- et al.
Human B7-1 (CD80) and B7-2 (CD86) bind with similar avidities but distinct kinetics to CD28 and CTLA-4 receptors
Immunity
(1994) - et al.
Covalent dimerization of CD28/CTLA-4 and oligomerization of CD80/CD86 regulate T cell costimulatory interactions
J Biol Chem.
(1996) - et al.
CTLA-4 can function as a negative regulator of T cell activation
Immunity
(1994) - et al.
Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties
Am J Transplant
(2005) - et al.
Cross-linking of OX40 ligand, a member of the TNF/NGF cytokine family, induces proliferation and differentiation in murine splenic B cells
Immunity
(1995) Biological therapies: a novel approach to the treatment of autoimzmune disease
Am J Med
(1995)- et al.
B lymphocytes and lupus nephritis: new insights into pathogenesis and targeted therapies
Kidney Int
(2008) - et al.
Binding of the B cell activation antigen B7 to CD28 costimulates T cell proliferation and interleukin 2 mRNA accumulation
J Exp Med
(1991) - et al.
Complementarity determining region 1 (CDR1)- and CDR3-analogous regions in CTLA-4 and CD28 determine the binding to B7-1
J Exp Med
(1994) - et al.
CD28 induces immunostimulatory signals in dendritic cells via CD80 and CD86
Nat Immunol
(2004)