Table 3.
Summary of the molecular and biological functions of T cell costimulatory molecules.
| Molecular marker | Aliase(s) | Ligand(s) | Receptor expression pattern | Biological function | Molecular function |
|---|---|---|---|---|---|
| Coinhibitory | |||||
| PD-1 | PDCD1, CD279, SLEB2, hPD-1 | PD-L1, PD-L2 | Activated T cells, NK cells, NKT cells, B cells, macrophages, subsets of DCs | Negative T cells costimulation (primarily in periphery), attenuate peripheral activity, preserve T-cell function in the context of chronic antigen | Inhibition of proximal TCR signaling, attenuate CD28 signaling |
| CTLA-4 | CD152, ALPS5, CELIAC3, GRD4 | B7-1 (CD80), B7-2 (CD86) | Activated T cells, Tregs | Negative T-cell costimulation (primarily at priming); prevent tonic signaling, attenuate high-affinity clones | Competitive inhibition of CD28 costimulation (binding to B7-1 and B7-2) |
| PD-L1 | CD274, PDCD1L1, B7-H, B7H1 | PD-1, B7-1 (CD80) | Monocytes, macrophages, mast cells, inducible in DCs, T cells, B cells, NK cells | Attenuate T cells activity in inflamed peripheral tissues | PD-1 ligation; cell-intrinsic mechanism unclear |
| LAG-3 | CD223, Ly66 | MHC-II, LSECtin | Activated CD4+ and CD8+ T cells, NK cells, Tregs | Negative regulator of T cells expansion; control T cells homeostasis; DCs activation | Competitive binding to MHC-II; proximal LSECtin mechanism unclear |
| TIM-3 | HAVCR2, CD366, KIM-3, SPTCL, TIMD-3 | Galectin-9, PtdSer, HMGB1, CEACAM-1 | Th1 CD4+ and Tc1 CD8+, Tregs, DCs, NK cells, monocytes | Negative regulation of Type immunity; preserve peripheral tolerance | Negative regulation of proximal TCR components; differences between ligands unknown |
| TIGIT | VSIG9, VSTM3, WUCAM | PVR (CD155), PVRL2 (CD112) | CD4+ and CD8+ T cells, Tregs, TFH, NK cells | Inhibition of T cells activity; DC tolerization | Competitive inhibition of DNAM1 (CD226) costimulation (binding of PVR), binding of DNAM1 in cis; cell-intrinsic ITIM-negative signaling |
| VISTA | VSIR, B7-H5, B7H5, C10orf54, PD-1H | Counterreceptor unknown | T cells and activated Tregs, myeloid cells, mature APCs | Negative regulation of T cells activity; suppression of CD4+ T cells, shaping naive CD4+ T cells compartment | Increase threshold for TCR signaling, induce FOXP3 synthesis; proximal signaling unknown |
| Costimulatory | |||||
| ICOS | AILIM, CCLP, CRP-1 | ICOSL | Activated T cells, B cells, ILC2 | Positive costimulation; Type I and II immunity; Tregs maintenance; TFH differentiation | p50 PI3K recruitment (AKT signaling); enhance calcium signaling (PLCγ) |
| OX40 | TNFRSF4, ACT35, CD134, TXGP1L | OX40L | Activated T cells, Tregs, NK cells, NKT cells, neutrophils | Sustain and enhance CD4+ T cell immunity; role in CD8+ T cells and Tregs | Regulation of BCL2/XL (survival); enhance PI3K/AKT signaling |
| GITR | TNFRSF18, AITR, CD357, ENERGEN, GITR | GITRL | Activated T cells, Tregs, B cells, NK cells, macrophages | Attenuate Tregs; costimulation of activated T cells, NK cell activation | Signal through TRAF5 |
| CD137 | TNFRSF9, 4-1BB, CDw137, ILA | 4-1BBL (CD137L) | Activated T cells, Tregs, NK cells, monocytes, DCs, B cells | Positive T cells costimulation; DC activation | Signal through TRAF1, TRAF2 |
| CD40 | TNFRSF5, Bp50, CDW40, p50 | CD40L | APCs, B cells, monocytes, non hematopoietic cells (e.g., fibroblasts, endothelial cells) | APC licensing | Signal through TRAF2, 3, 5, 6; TRAF-independent mechanisms unclear |
| CD27 | TNFRSF7, S152, LPFS2, Tp55 | CD70 | CD4+ and CD8+ T cells, B cells, NK cells | Lymphocyte and NK cell costimulation; generation of T-cell memory | Signal through TRAF2, TRAF5 |
A summary of the ligands, immune-related expression pattern, biological function, and molecular mechanisms is reviewed 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.
NK, natural killer; NKT, natural killer T cell; TFH, T follicular helper; TRAF, tumor necrosis factor receptor–associated factors; DC, dendritic cell.