CD28 Family and Chronic Rejection: “To Belatacept...and Beyond!”

Table 1

Expression of CD28 family members, ligands, and targeting in transplantation.

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]