Historical evolution, overview, and therapeutic manipulation of co-stimulatory molecules

Table 1 Immunoglobulin super family co-stimulatory molecules

IgSF co-stimulatory molecules	Function	Cells expressing the receptor	Ligand	Cells expressing the ligand
CD28	Activation	Constitutive in T cells	CD80, CD86	CD80: Inducible in dendritic cells, monocytes, B and T cells. CD86: Constitutive in dendritic cells, monocytes, B and T cells
ICOS (CD278)	Activation	Inducible in T, B, and NK cells	ICOSL	Constitutive in macrophages, dendritic cells, B and T cells
CTLA-4 (CD152)	Inhibition	Inducible in T cells	CD80, CD86	CD80: Inducible in dendritic cells, monocytes, B and T cells. CD86: Constitutive in dendritic cells, monocytes, B and T cells
PD-1 (CD279)	Inhibition	Inducible in T, and B cells, macrophages	PD-L1, PD-L2	PD-L1: Constitutive in dendritic cells, B and T cells. PD-L2: Inducible in dendritic cells and monocytes
PD-1H (VISTA)	Inhibition	Monocytes, neutrophils, T cells	Unknown	Unknown
BTLA (CD272)	Inhibition	B and T cells	HVEM, UL144	Monocytes, B and T cells
B71 (CD80), B72 (CD86)	Activation/Inhibition	CD80: Inducible in dendritic cells, monocytes, B and T cells. CD86: Constitutive in dendritic cells, monocytes, B and T cells	CD28, CTLA-4	CD28: Constitutive in T cells. CTLA-4: Inducible in T cells
B7H1 (CD274, PDL1)	Inhibition	Constitutive in dendritic cells, monocytes, B and T cells	PD-1, B71	PD-1: Inducible in macrophages, B and T cells. CD80: Inducible in dendritic cells, monocytes, B and T cells

BTLA: B- and T lymphocyte attenuator; CTLA: Cytotoxic T lymphocyte antigen; HVEM: Herpes virus entry mediator; ICOS: Inducible T cell co-stimulator; ICOSL: Inducible T cell co-stimulator ligand; PD-1: Programmed death-1; PD-L: Programmed death ligand; PD-1H: Programmed death-1 homolog; VISTA: V domain Ig suppressor of T cell activation.

Table 2 Tumor necrosis factor receptor super family co-stimulatory molecules

TNFR SF co-stimulatory molecules	Function	Cells expressing the receptor	Ligand	Cells expressing the ligand
OX40 (CD134)	Activation	Activated and regulatory T cells	OX40L	T cells, macrophages, endothelial cells, vascular smooth muscle cells, dendritic cells, tumor cells
CD27 (TNFR SF7)	Activation	T and B cells, NK cells	CD70	NK, T and B cells
GITR (CD357)	Activation	T cells	GITRL	T cells
CD30 (TNFR SF8)	Activation	T and B cells	CD30L	T cells
HVEM (CD270)	Activation	Monocytes, T and B cells	LIGHT, BTLA, CD160, LTα3, HSV1gD	Monocytes and APCs
FAS (CD95)	Activation	NK and T cells	FASL	Dendritic cells, NK, T cells, neutrophils
CD40 (TNFR SF5)	Activation	All B-cell lineages except plasma cells, macrophages, activated monocytes, follicular dendritic cells, interdigitating dendritic cells, endothelial cells, fibroblasts	CD40L	Activated CD4+ T cells, some CD8+ T cells, γδ T cells, basophils, platelets monocytes and mast cells
RANK (CD265)	Activation	Osteoclast and dendritic cells	RANKL	Osteoblasts, T cells
TACI (CD267)	Inhibition	B and plasma cells	BAFF, APRIL	Stromal cells, dendritic cells, and macrophages

APCs: Antigen-presenting cells; APRIL: A proliferation-inducing ligand; BAFF: B-cell activating factor; BTLA: B- and T lymphocyte attenuator; FASL: FAS ligand; GITR: Glucocorticoid-induced TNFR-related protein; HSV1gD: Herpes simplex virus-1 glycoprotein D; HVEM: Herpes virus entry mediator; LIGHT: TNFR14; LT3: Lymphotoxin-alpha 3; RANK: Receptor activator of nuclear factor kappa; TACI: Transmembrane activator and calcium-modulator and cyclophilin ligand interactor; TNFR SF: Tumor necrosis factor superfamily.

Table 3 Immunoglobulin super family co-stimulatory molecules studied in various diseases

Molecule	Disease	Alteration	Ref.
CD86	Rheumathoid arthritis	Increased expression in B cells	[16]
ICOSL	Combined immunodeficiency	Mutation	[17]
CTLA-4	Mycosis fungoides	Increased expression in T cells	[18]
CD28	Tuberculosis	Decreased expression in CD8+ and CD4+ T cells	[19]
CD28	Graves’ disease	Increased expression in T cells	[20]

CTLA: Cytotoxic T lymphocyte antigen; ICOSL: Inducible T cell co-stimulator ligand.

Table 4 Tumor necrosis factor superfamily co-stimulatory molecules studied in various diseases

Molecule	Disease	Alteration	Ref.
CD27	Lupus erythematosus	Increased expression in plasmablasts	[21]
CD70	Lupus erythematosus	Increased expression in plasmablasts	[21]
CD40	Hyper IgM Syndrome	Mutations	[22]
CD30	Vernal Keratoconjunctivitis	Increased expression in T cells	[23]
CD267	Common variable immunodeficiency	Mutations	[24]

Table 5 Co-stimulatory molecule manipulation in various diseases

Disease	Therapeutic target	Manipulation	Outcome	Ref.
Brain metastases melanoma	PD-1 and CTLA-4	Blockade with mAbs (nivolumab + ipilimumab)	55% of treated patients reduced tumor size. 21% showed full response	[27]
Melanoma	PD-1	Blockade with mAbs (pembrolizumab or nivolumab)	19% of treated patient reduced tumor size	[28]
Melanoma	PD-1	Blockade with mAbs (pembrolizumab)	33% of treated patient reduce size tumor	[29]
Rheumatoid arthritis	CD80/CD86	Blockade with soluble receptor (abatacept)	Reduction in the disease index	[30]
Psoriatic arthritis	CD80/CD86	Blockade with soluble receptor (abatacept)	Musculoskeletal clinical improving	[31]
Sjögren syndrome	CD40	Blockade with recombinant antibody (CFZ533 or iscalimab)	Reduction in the disease index	[32]
Kidney graft	CD40	Blockade with recombinant antibody (CFZ533 or iscalimab)	Transplant success rate similar to tacrolimus treatment, but with a lower probability of adverse effects and infections	[33]

CTLA: Cytotoxic T lymphocyte antigen; PD-1: Programmed death-1.