Table 1.

Costimulatory pathways and their role in transplantation (reviewed in 93–96).

Receptor/ Ligand(s)	Expression	Function	Role in transplantation
CD28/ CD80 and CD86	CD28–all naïve T cells CD80 – inducible on APCs CD86 – constitutive on APCs, up-regulated upon activation	Key costimulatory pathway regulating proliferation, survival and effector functions of activated T cells.	Targeting this pathway prolongs allograft survival in multiple rodent models. CD80 and CD86 blockade with CTLA4-Ig-like reagents improves allograft outcome in pre-clinical primate models and is currently in clinical trial.
CD154/ CD40	CD154 – activated CD4 T cells, NK cells, platelets CD40 – constitutive on APCs, can be induced on endothelial and parenchymal cells	Amplifies T cell responses through activation of dendritic cells, provides helper signals to B cells.	Anti-CD154 antibody treatment efficiently prevents allograft rejection in naïve but not sensitized rodents. Tromboembolic side effects of anti-CD154 antibody in non-human primates and humans has prompted the development of CD40-targeting reagents.
ICOS/ B7RP-1	ICOS – activated T cells, resting memory CD4 T cells B7RP-1 – constitutive on APCs, B cells, parenchymal and endothelial cells; up- regulated upon activation	Effector functions of activated T cells, Th2 differentiation, antibody production, transendothelial migration of T lymphocytes.	ICOS blockade is beneficial for allograft survival in rodent models, especially when combined with other costimulation-blocking reagents. Targeting ICOS/B7RP-1 decreases production of donor-reactive alloantibody, inhibits infiltration of effector T cells into the graft and prevents early intragraft cytokine production by pre-existing memory CD8 T cells.
CD134/ CD134L	CD134 – activated T cells, Foxp3+ regulatory T cells CD134L – dendritic cells, B cells, activated endothelial cells	Co-stimulates T cell activation and differentiation; promotes generation and survival of memory T cells; inhibits suppressive functions of regulatory T cells.	Anti-CD134L antibody treatment synergizes with CD28/CD80 and CD86 and with CD40/CD154 costimulatory blockade to prolong heart and islet allograft survival in rodents and to prevent skin allograft rejection mediated by memory T cells.
CD27/ CD70	CD27– naïve T cells, B cells, NK cells CD70- APCs, activated T and B cells	Supports T cell development, activation, T/B cell interaction and antibody production, anti-viral NK cell function.	In the absence of CD28 costimulation, CD70 blockade prolongs survival of murine cardiac allografts by inhibitng activation of alloreactive CD8 T cells.
PD-1/ PD-L1/2	PD-1 – activated T and B cells, NK cells macrophages PD-L1/2 – up-regulated on activated APCs; PD-L1 is constitutively expressed on parenchymal cells and induced on activated endothelial cells.	Negatively regulates T cell expansion and effector functions.	Anti-PD-L1 antibody treatment leads to enhanced alloresponses and accelerated allograft rejection. Conversely, signaling through PD-1 works in synergy with anti- CD154 therapy to prevent murine islet allograft rejection.
4-1BB/ 4-1BBL NK cells	4-1BB – activated T cells (especially CD8 T cells) and NK cells 4-1BB – dendritic cells, macrophages, activated B cells	Promotes T cell survival, differentiation and effector functions, may enhance functions of memory CD8 T cells.	Blocking 4-1BB pathway delays small bowel allograft rejection mediated by CD8 T lymphocytes. In contrast, stimulating signals through 4-1BB accelerate graft rejection in this model.