Table 1

Mechanisms of action for the B7:CD28/CTLA-4 pathway (1737).

Extrinsic control of immune activation by CTLA-4
MechanismOutcomeReference(s)
Reverse signaling through CD80 and CD86 on APCsActivation of the tryptophan-degrading enzyme IDO leads to suppression of T cell responses by reducing tryptophan levels and/or promoting conversion of naïve T Cells to TregGrohmann U, et al.(17)
Fallarino F, et al.(18)
Munn DH, et al. (19)
Mellor AL, et al.(20)
Orabona C, et al. (21)
CTLA-4 signaling stimulates the production of regulatory cytokines, such as TGF-βTGF-β secretion results in inhibition of antigen presentation by APCs and T cell functionChen W, et al. (22)
CTLA-4 binding to CD80 or CD86 reduces the availability of these ligands to engage CD28Reduced ability of APCs to stimulate functional T cell responses leads to greater threshold of activationLinsley PS, et al. (23)
Walunas TL, et al. (24)
Oaks MK, Hallet KM (25)
CTLA-4 binding to CD80 or CD86 can cause transendocytosis of these ligandsDegradation of co-stimulatory ligands results in decreased APC functionQureshi OS, et al. (26)
Intrinsic control of immune activation by CTLA-4
Recruitment of inhibitory proteins toT cell synapseRecruitment of PP2A and PTPN11 to T cell synapse interferes with proximal signaling by either the TCR or CD28, resulting in inhibition of TCR and CD28 proximal signalsChuang E, et al.(27)
Parry RV, et al.(28)
Marengere LE, et al. (29)
Ligand competition prevents CD28 signalingCTLA-4 may prevent CD28 from generating positive signals by acting as a high-affinity competitor for ligandsThompson CB, Allison JP (30)
Non-ligand binding CTLA-4 splice variantA splice variant of CTLA-4 that cannot bind lo ligands may inhibit T cell activation through an inhibitory signaling pathway, reminiscent to that of the full-length moleculeVijayakrishnan L, et al. (31)
Araki M, et al. (32)
Chikuma S, et al. (33)
Choi JM, et al. (34)
Choi JM, et al.(35)
Inhibition of T cell stop signalIncreased T cell motility and inhibition of TCR-induced stop signal is required for stable conjugate formation between T cells and APCs. This event leads to reduced contact periods between T cells and APCs that in turn decrease cytokine production and proliferationSchneider H, et al.(36)
Schneider H, et al.(37)