Summary of the biological and molecular functions of T-cell costimulatory molecules
| Molecule | Ligand(s) | Receptor expression pattern | Biological function | Molecular function | References | ||
|---|---|---|---|---|---|---|---|
| Coinhibitory | |||||||
| CTLA4 | B7-1 (CD80), B7-2 (CD86) | Activated T cells, Treg | Negative T-cell costimulation (primarily at priming); prevent tonic signaling and/or attenuate high-affinity clones | Competitive inhibition of CD28 costimulation (binding of B7-1 and B7-2) | (8, 10–12, 38, 157–161) | ||
| PD-1 | PD-L1, PD-L2 | Activated T cells, NK cells, NKT cells, B cells, macrophages, subsets of DC; as a result of inflammation | Negative T-cell costimulation (primarily in periphery); attenuate peripheral activity, preserve T-cell function in the context of chronic antigen | Attenuate proximal TCR signaling, attenuate CD28 signaling | (32–35, 38, 39, 53, 100, 162–165) | ||
| PD-L1 | PD-1, B7-1 (CD80) | Inducible in DC, monocytes, macrophages, mast cells, T cells, B cells, NK cells | Attenuate T-cell activity in inflamed peripheral tissues | PD-1 ligation; cell-intrinsic mechanism unclear | (33, 34, 102) | ||
| LAG3 | MHC-II, LSECtin | Activated CD4 and CD8 T cells, NK cells, Treg | Negative regulator of T-cell expansion; control T-cell homeostasis; DC activation | Competitive binding to MHC-II; proximal LSECtin mechanism unknown | (133, 134, 166–170) | ||
| TIM3 | Galectin-9, PtdSer, HMGB1, CEACAM-1 | Th1 CD4 and Tc1 CD8, Treg, DC, NK cells, monocytes | Negative regulation of Type 1 immunity; maintain peripheral tolerance | Negative regulation of proximal TCR components; differences between ligands unclear | (135–139, 171) | ||
| TIGIT | PVR (CD155), PVRL2 (CD112) | CD4 and CD8, Treg, TFH, NK cells | Negative regulation of T-cell activity; DC tolerization | Competitive inhibition of DNAM1 (CD226) costimulation (binding of PVR), binding of DNAM1 in cis; cell-intrinsic ITIM-negative signaling | (144, 145, 172–176) | ||
| VISTA | Counter-receptor unknown | T cells and activated Treg, myeloid cells, mature APC | Negative regulation of T-cell activity; suppression of CD4 T cells | Increase threshold for TCR signaling, induce FOXP3 synthesis; proximal signaling unknown | (140, 141, 146, 147, 177, 178) | ||
| Costimulatory | |||||||
| ICOS | ICOSL | Activated T cells, B cells, ILC2 | Positive costimulation; Type I and II immune responses; Treg maintenance; TFH differentiation | p50 PI3K recruitment (AKT signaling); enhance calcium signaling (PLCγ) | (179–186) | ||
| OX40 | OX40L | Activated T cells, Treg, NK cells, NKT cells, neutrophils | Sustain and enhance CD4 T-cell responses; role in CD8 T cells and Tregs | Regulation of BCL2/XL (survival); enhance PI3K/AKT signaling | (187–193) | ||
| GITR | GITRL | Activated T cells, Treg, B cells, NK cells, macrophages | Inhibition of Tregs; costimulation of activated T cells, NK cell activation | Signal through TRAF5 | (194–200) | ||
| 4-1BB (CD137) | 4-1BBL | Activated T cells, Treg, NK cells, monocytes, DC, B cells | Positive T-cell costimulation; DC activation | Signal through TRAF1, TRAF2 | (201–205) | ||
| CD40 | CD40L | APCs, B cells, monocytes, nonhematopoietic cells (e.g., fibroblasts, endothelial cells) | APC licensing | Signal through TRAF2, 3, 5, 6; TRAF-independent mechanisms? | (206–209) | ||
| CD27 | CD70 | CD4 and CD8 T cells, B cells, NK cells | Lymphocyte and NK cell costimulation; generation of T-cell memory | Signal through TRAF2, TRAF5 | (210–214) | ||
NOTE: A summary of the ligands, immunologic expression pattern, biological function, and molecular mechanisms is presented for selected costimulatory and coinhibitory receptors. Molecular functions (i.e., downstream signaling) reflect predominant currently known mechanisms, but additional mechanisms are likely to contribute significantly.
Abbreviations: NK, natural killer; NKT, natural killer T cell; TFH, T follicular helper; TRAF, tumor necrosis factor receptor–associated factors; DC, dendritic cell.