| Receptor
(Ligand) |
Intracellular motif |
Mechanism of Action |
Receptor distribution |
Ligand distribution |
Disease |
Biologic
(Target) |
Refs. |
| CTLA-4
(CD80, CD86) |
YxxM |
1Use of intracellular mediators–SHP-2, PI3K
3Ectodomain competition–with counter receptor (CD28); interference of lipid-raft and microcluster formation |
Activated T cells |
B cells, Mo, DCs, T cells, inducible in some somatic tissues |
RA, MS, LN, Melanoma |
abatacept (B7) ipilimumab (CTLA-4) tremelimumab (CTLA-4) |
[31,89]
[13,90]
[34,91] |
| PD-1
(PD-L1, PD-L2) |
ITIM, ITSM |
1Use of intracellular mediators– recruitment of SHP-1, SHP-2; suppression of transcription factor SKP2
2Inducing genes that negatively regulate T cell signalling– BATF |
Activated T cells, B cells, DCs, NKT cells, Mo |
B cells, T cells, inducible in Mo, DCs, some somatic tissues |
Melanoma, RCC, HIV |
CT-011(PD-1) MDX1106 (PD-1) MPDL3280A (PD-L1) |
[41,92]
[93,94]
[95] |
| BTLA (HVEM) |
ITIM, ITSM |
1Use of intracellular mediators–SHP-1, SHP-2
3Ectodomain competition with counter receptor (LIGHT) |
T cells, B cells, DCs, Myeloid cells |
naive T cells, B cells, DCs, NK cells, myeloid cells, inducible in somatic tissues |
GVHD, Autoimmune diabetes |
N/A |
[51,52] |
| LAG-3
(MHC II) |
KIEELE |
3Ectodomain competition with counter receptor (CD4) |
T cells, B cells, NK cells |
DCs, MΦ, B cells, Mo, thymic epithelial cells |
Melanoma, RCC |
IMP321 (MHC II) |
[96,97]
[58] |
| TIM-3
(Galectin-9, PS) |
Y235, Y242 |
1Use of intracellular mediators–Lck, Fyn, p85 PI3K, Bat3 (repressor of TIM-3 signalling) |
T cells, B cells, NK cells, NKT cells, DCs, MΦ |
T cells, eosinophils, endothelial cells, DCs, MΦ |
MS, colitis, HIV, HCV |
N/A |
[66,69]
[64,70] |
| LAIR-1
(Collagen) |
2×ITIM |
1Use of intracellular mediators–SHP-1, SHP-2, Csk |
T cells, B cells, NK cells, DCs, Mo, eosinophils, Basophils, Mast cells |
Extracellular matrix components |
RA |
N/A |
[71] |
| TIGIT
(CD155) |
2×ITIM |
3Ectodomain competition with the counter receptor (CD266) |
T cells, NK cells |
T cells, B cells, DCs |
MS |
N/A |
[77,78] |
| Siglecs
(sialylated glycoconjugates) |
variable number of ITIM, Grb2 and ITIM-like domains |
1Use of intracellular mediators–SHP-1, SHP-2, PI3K
3Ectodomain competition with the counter receptor (cis/trans-ligand binding) |
T cells, B cells, DCs, pDCs, MΦ, Mo, Neutrophils, NK cells, eosinophils |
widespread on cell surfaces, proteins, pathogens |
Leukaemia, SLE, B cell-NHL |
gemtuzumab (Siglec-3), epratuzumab (Siglec-2) |
[98,99] |
Abbreviations: 1-3 three general types of distinct mechanisms of action; B cell-NHL: B cell non Hodgkin’s Lymphomas; Bat3- Human Leukocyte Antigen B (HLA-B)-associated
Transcript 3; BATF: Basic Leucine Zipper Transcription Factor, ATF-like; BTLA: B- and T-lymphocyte Attenuator; Csk: COOH-terminal; CTLA-4: Cytotoxic T-Lymphocyte
Antigen 4; DC: Dendritic Cells; Fyn: a Src family tyrosine-protein kinase; Grb2: Growth factor receptor-bound protein 2; GVDH: Graft Versus Host Disease; HCV: Hepatitis C
Virus; HIV: Human Immunodeficiency Virus; HVEM: Herpes Virus Entry Mediator; ITIM- Immunoreceptor Tyrosine-based Inhibition Motif; ITSM: Immunoreceptor Tyrosinebased
Switch Motif; LAG-3: Lymphocyte-Activation Gene 3; LAIR-1: Leukocyte-Associated Immunoglobulin-like Receptor 1; Lck: Lymphocyte-specific protein tyrosine
kinase; LIGHT: Lymphotoxin-like, exhibits inducible expression, and competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed by T lymphocytes;
LN: Lupus Nephritis; MHC II: Major Histocompatibility Complex II; Mo: Monocyte; MS: Multiple Sclerosis; MΦ: Macrophage; N/A: Not Applicable; NK: Natural Killer cells;
NKT: Natural Killer T cells; PD-1: Programmed cell death protein 1; pDC: plasmacytoid dendritic cell; PD-L1: Programmed cell death 1 ligand 1; PI3K: Phosphoinositide
3-kinase; PS: Phosphatidyl Serine; RA: Rheumatoid Arthritis; RCC: Renal Cell Carcinoma; SHP-1/2/: Src homology 2-containing tyrosine phosphatase 1/2/; Siglecs: Sialic
acid binding Ig-like lectins; SLE: Systemic Lupus erythematous, Srk kinase; SKP2: S-phase Kinase-associated Protein 2; TIGIT: T-cell immunoreceptor with immunoglobulin
and ITIM domains; TIM-3: T cell Immunoglobulin Mucin-3 |
