Table 1. Summary of costimulatory molecules.

Molecule	Expression	Ligand(s)	Expression	Function	Drugs/mAb
CD28	T cells, thymocytes, NK eosinophils and melanoma cells [6,8,11,12]	CD80 (B7-1) CD86 (B7-2)	Upregulated on activated DCs [13], B cells and macrophages [6] Upregulated on activated monocytes, DCs and B cells, T cells and APCs [6]	Enhances T-cell proliferation and cytokine production through induction of IL-2 expression [6] Promotes T-cell differentiation into IL-4-producing T-helper 2 cells [6,14] Stimulates B cells for antibody production [8] Augments the kinetics and level of expression of OX40, 4–1BB and CD30 [6,15] Inhibition of CD28/B7 reduces specific Ab production, prolongs the survival of organ transplants and inhibits autoimmune diabetes and lupus	Abatacept (CTLA-4-Ig) targeting CD80/86 has been approved by FDA to use in RA. It is also in Phase II clinical trials in psoriasis [16-19] Belatacept (CTLA-4-Ig) has clinical indication in renal transplantation [20,21] Galiximab is an anti-CD80 mAb. It has a clinical indications in non-Hodgkin’s B-cell lymphoma [22] and psoriasis [16]. It is now in Phase III clinical trials [201]
PD-1	B cells, monocytes/ macrophages and activated T cells [23]	PDL-1 (B7-H1) PDL-2 (B7-DC)	Found on nonhematopoietic cells [23] T cells, B cells, dendritic cells and macrophages [23,24]	Transmits signals that inhibit T- and B-cell activation [23]	PDL-1-Ig fusion protein reduced clinical score in collagen induced arthritis mouse model and prolonged graft surviva in mice [23,25] Anti-PD-1 antibody antagonists (MDX-1106, CT-011) are currently in Phase I clinical trials in melanoma [26,27,201]
CTLA-4 (CD152)	Activated T cells [14]	B7-1 (CD80) and B7-2 (CD86)	T cells, B cells, macrophages, DCs, endothelial cells, epithelial cells and fibroblasts [14]	Transmits an inhibitory signal to T cells and inhibits T-cell activation [14] Depletes the expression of IL-2 and IL-2R [8] CTLA-4 binds B7 with a much higher affinity than CD28	Anti-CTLA-4 mAb (Ipilimumab and tremelimumab) have clinical indications in melanoma and other tumors. They have been studied in Phase II/III clinical trials [28-31,201]
ICOS (CD278)	Activated T cells [32]	ICOSL (B7RP-1 or CD275)	Constitutively expressed on B cells, dendritic cells, monocytes, endothelial cells, fibroblasts and epithelial cells [32]	Enhances T-cell differentiation, cytokine production and survival [32]	Anti-ICOSL mAb antagonist has been shown to reduce the severity of G6PI-induced arthritis [33], reduce lethality and symptoms in GVHD in mice [34] Anti-ICOS mAb prolongs cardiac and bone marrow graft survival in mice [35-37]
BTLA (CD272)	B cells and inducible during activation of T cells [38,39]	HVEM	Naive or resting T cells, NK cells, B cells and DCs, myeloid cells [38,39]	Delivers the inhibitory signal of T-cell activation [38,39] Decreases IL-2 production [38,39] Balances activation and inhibition during an immune response [40]	Anti-BTLA in a combination with CTLA-4-Ig has shown efficacy in allograft rejection [41,42]
CD40	B cells, monocytes, macrophages, DCs, platelets and inducibly expressed on non-hematopoietic cells such as epithelial and endothelial cells and fibroblasts [43]	CD40L (CD154)	Activated T cells, activated B cells and platelets [43]	Promotes B-cell activation and DC maturation [8] Induces memory B cells maturation [43,44] CD40 ligation leads to the upregulation of B7-1 and B7-2 on APCs and enhances the ability of APCs to activate naive T cells [43,44]	Dacetuzumab (anti-CD40 mAb) has been shown that it has an immunosuppressive effect in multiple myeloma, non-Hodgkin’s lymphoma (Phase I) [45,46], diffuse large B-cell lymphoma [47] and chronic lymphocytic leukemia (Phase I) [48] Anti-CD40L mAb significantly suppressed T-cell-mediated alloimmune responses and prolonged allograft survival in monkeys [44] and has been studied in clinical trials for lupus nephritis and kidney transplantation (Phase II) [201]
OX40 (CD134)	Activated T cells [15]	OX40L (CD252)	Professional APCs, can be induced on activated B cells, mature DCs, plasmacytoid DCs and macrophages [15]	Promotes T-cell proliferation, differentiation, survival, cytokine production and effector cell function of T cells [15] OX40–OX40L interactions additionally modulate the differentiation and activity of regulatory T cells (both suppress and promote proliferation of these cells) [15]	Anti-OX40 and -OX40L mAb agonists have shown benefits in cancer. Anti-OX40 mAb was studied in clinical trials (Phase I/II) [49-51,201]. There is an onging clinical study of human mAb OX40L for treatment of asthma (Phase II) [201] Neutralizing anti-OX40L ameliorated the severity of disease in experimental autoimmune encephalomyelitis [52], colitis [53], arthritis [54], asthma [55] and diabetes [56] in vivo
GITR	Naive T cells and Treg It is upregulated on effector T cells [57] and on tissue infiltrating macrophages	GITRL	B cells, macrophages, DCs, endothelial cells thymic precursors and activated T cells [57]	Suppresses function of Treg [58] Activates effector T cells and NK cells [58] Induces inflammatory activation of macrophage [57]	Anti-GITR mAb agonist induced antitumor immunity [59,60] Phase I clinical study is being performed for treatment of malignant melanoma [201] GITR fusion protein binding to GITRL prolonged allograft survival and showed potential anti-inflammatory properties in animal studies [61,62] Neutralizing anti-GITRL mAb protected the progression of diabetes [63]
CD27	Naive T cells, B cells, NK cells, memory and antigen-exposed T cells [64,65]	CD70	Activated T cells, B cells, macrophages, and activated DCs [64,65]	Stimulates T-cell activation, expansion and survival [66] Promotes B-cell activation and production of antibodies [64]	Anti-CD70 mAb agonist exhibited antitumor immunity in in vivo studies [67,68] Neutralizing anti-CD70 mAb improved disease severity in inflammatory and autoimmune disease [69,70]
LIGHT (TNFSF14)	Activated T cells and immature DCs [65,71]	HVEM (this is the receptor)	T cells, B cells, DCs, macrophages and NK cells [65,72]	Promotes T-cell proliferation, cytokine production, and activation of NF-κB [8]	LTβR-Ig fusion protein has been shown to ameliorate trinitrobenzene sulfonic acid-induced colitis and prolonged survival of GVHD mice [73] Anti-HVEM mAb profoundly ameliorated GVHD in mice [74] HVEM-Ig fusion protein plus cyclosporine A prolonged allograft survival in mice [75]
4–1BB (CD137)	Activated T cells and NK cells [76-78]	4–1BBL	Activated DCs, B cells and macrophages [76-78]	Provides costimulation of T-cell activation and promotes T-cell survival [76-78]	Anti-4–1BB mAb agonist has shown to have anti-tumor immunity in vivo [79]. It is now being studied in Phase II clinical trials [201] Neutralizing anti-4–1BBL mAb attenuated acute rejection in rat liver transplantation [80]
VLA-4	T cells, B cells, monocytes, NK cells, eosinophils, neutrophils and hematopoietic cells [78]	VCAM-1 (CD106) and fibronectin	Endothelial cells [78]	Regulates adult hematopoiesis [78] Promotes the adhesion of lymphocytes, monocytes, eosinophils and basophils [8]	Natalizumab (anti-VLA-4 antagonist) was approved by FDA for the treatment of relapsing forms of multiple sclerosis [81]
LFA-1	Leukocytes [82]	ICAM-1 (CD54) and ICAM-2 (CD102)	Vascular endothelium, macrophages and lymphocytes [8]	Mediates adhesive interaction between T cells and APCs in the immunological synapse and mediates leukocyte trafficking during inflammation [82]	Efalizumab (anti-LFA-1 mAb) was approved to use in psoriasis but withdrawn due to an increased risk of PML [83] Anti-ICAM-1 mAb was studied in Phase III clinical trials for Crohn’s disease (alicaforsen) [84,201]and ischemic stroke (enlimomab) [85] None of them were continued in the post-marketing phase
Mac-1	Leukocytes [82]	ICAM-1 (CD54)	Vascular endothelium, macrophages, and lymphocytes [8]	Mediates leukocyte trafficking during inflammation and contributes to leukocyte activation in immune responses [82]	Anti-Mac-1 showed no effect in graft survival [86]

APC: Antigen-presenting cell; BTLA: B- and T-lymphocyte attenuator; DC: Dendritic cell; GVHD: Graft-versus-host disease; HVEM: Herpes virus entry mediator; ICOS: Inducible costimulator; LFA: Leukocyte function-associated antigen; mAb: Monoclonal antibody; PD: Programmed death; PML: Progressive multifocal myeloencephalopathy; RA: Rheumatoid arthritis.