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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 3. Comparison of intracellular signaling by CTLA-4 and PD-1.

Figure 3

PD-1 and CTLA-4 both inhibit Akt activation, but they target different signaling molecules. CTLA-4 engagement by its ligands CD80 and CD86, activates the serine/threonine phosphatase PP2A, which directly inhibits the TCR/CD28-mediated activation of Akt, but preserves PI3K activity, and therefor expression of Bcl-xL. PD-1 ligation by PD-L1 or PD-L2 leads to phosphorylation of ITSM/ITIM motifs in the PD-1 cytoplasmic domain, which results in recruitment of the tyrosine phosphatases SHP-1 and SHP-2, and inhibition of PI3K activity and therefor reduced expression of Bcl-xL. PD-1 ligation also inhibits PLCγ1 and downstream Ras-MEK-ERK signaling and leads to upregulation of the pro-apoptotic molecule BIM. In contrast to PD-1, CTLA-4 does not inhibit Ras-MEK-ERK and PLCγ1 signaling.