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. Author manuscript; available in PMC: 2017 May 17.
Published in final edited form as: Immunity. 2016 May 17;44(5):955–972. doi: 10.1016/j.immuni.2016.05.002

Figure 2. Regulation of CTLA-4 expression and functional effects of CTLA-4.

Figure 2

(a) Dynamics of CTLA-4 expression and membrane cycling. Following synthesis in the Trans Golgi Network (TGN), CTLA-4 binds to T cell receptor-interacting molecule (TRIM), promoting formation of CTLA-4-containing vesicles. TCR signaling-mediated calcium influx induces CTLA-4 release from the vesicles to the cell surface, and CTLA-4 and TRIM no longer associate. CTLA-4 externalization also depends on phospholipase D (PLD) and GTPase adenosine diphosphate ribosylation factor 1 (ARF-1). Unphosphorylated CTLA-4 cytoplasmic domain binds to the clathrin adapter protein 2 (AP-2) which promotes rapid internalization to endosomes and lysosomes. Tyrosine phosphorylation of the CTLA-4 cytoplasmic domain retards internationalization. Upon T cell activation, CTLA-4-containing endosomes are recycled to the cell surface; this is regulated by lipopolysaccharide-responsive and beige-like anchor protein (LRBA). Association of CTLA-4 with adapter protein 1 (AP-1) mediates shuttling from the TGN to lysosomal compartments for degradation, a mechanism that controls the overall abundance of CTLA-4 in the TGN.

(b) CTLA-4 can exert T cell-intrinsic and T cell-extrinsic functions. Intrinsic control. (1) Inhibitory signaling. Signals through CTLA-4 can interfere with proximal signaling by the T cell receptor (TCR) and CD28. (2) Competition for ligands. CTLA-4 is the higher affinity receptor than CD28 for CD80/CD86 and can outcompete CD28 for CD80/CD86 binding. (3) Promote adhesion or reduced stop signal. CTLA-4 can increase T cell/APC adhesion through a pathway mediated by LFA1 and decrease duration of APC/T cell interactions by inhibiting the TCR-mediated stop signal, resulting in reduced T cell activation. (4) Ligand-independent inhibition. A CTLA-4 splice variant that cannot bind to ligands may inhibit T cell activation through a similar signaling pathway as full length CTLA-4. Extrinsic control(1) Reverse signaling through ligands into APCs. CTLA-4 may reverse signal through CD80 and CD86 into APCs, leading to IDO production and suppression of T cell effector responses. (2) Reduce ligand expression/availability. Secreted factors such as IL10, TGFp or soluble splice variants of CTLA-4 reduce ligand expression or availability. (3) CTLA-4 removes ligands from APCs. CTLA-4 binding to CD80 or CD86 can result in transendocytosis of the ligands from the APC, resulting in lower levels of ligands on the surface of APCs.