| Receptor | CD28 | CTLA-4 | ICOS | PD-1 |
| Expression | Constitutive on T-cells | Induced on T-cells | Induced on Tcells after TCR and CD28 stimulation [44]. Th1, Th2, Th17, Tfh, and Treg lymphocytes [44–46] | T lymphocytes, B lymphocytes, monocytes and NK cells [47, 48] | | | | | | Ligand | CD80 (B7.1); CD81 (B7.2) | CD80 (B7.1); CD81 (B7.2) | ICOS-L (CD275, B7-H2, B7h, B7RP-1) | PD-L1 (CD274, B7-H1); PD-L2 (CD273, B7-DC) | | | | | | Ligand expression | APCs, activated dendritic cells (DC) B cells, T-cells, monocytes | APCs, activated dendritic cells (DC) B cells, T-cells, monocytes Nonlymphoid cells (liver, ling, kidney) | APCs, activated dendritic cells (DC) B cells, T-cells, monocytes Nonlymphoid cells (liver, lung, kidney) | DCs, T and B lymphocytes, mesenchymal stem cells, mast-cells and other nonhematopoietic cells [125, 126] | | | | | | Major role | Positive costimulation expression of antiapoptotic genes [49, 50] cell survival, proliferation, IL-2 production and potentiates the T-cell-dependent activation of B lymphocytes [51–54] | Negative costimulation Expression of the proapoptotic genes Production of immunoregulatory cytokines Peripheral tolerance [40, 51, 53, 55–58] | Positive costimulation induction of T-cell proliferation, augmented cytokine production [44, 59, 60] Generation and homeostasis of Treg cells [61, 62] | Negative costimulation [63, 64]. Inhibitor of cell proliferation and cytokine production [65–67]. Peripheral cell tolerance [68–70]. Suppression mediated by Treg [71] | | | | | | Role in Allograft Rejection | CD28−/−-delayed graft rejection [72, 73] CD28 co-stimulatory blockade—graft survival [74–77] | ↑ number of Treg cells [78, 79]. Augmented number of CTLA-4 molecules—↑ tolerance to allografts [80] CTLA-4-Ig—↓ proliferation of allospecific T-cells [81, 82]; prevent the rejection [83–85]; ↑ graft survival in human transplantation [86–90] | Allograft rejection [91] ICOS-Ig—↑ graft survival [64, 92–97]; ↓ kidney transplant survival [98] | Regulation of alloimmune responses in animal models [99–101]. Anti-PD-1 treatment—↑ graft survival anti-PD-L1 antibodies ↑ rejection process [101]. PD-L1 expression in transplanted tissues—tolerance to the graft [102] |
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