Fig. 2.

PD-1 signaling in T cells and macrophages. A Mechanisms of PD-1 signaling in T cells. PD-1 inhibits T cell function by recruiting phosphatases SHP-1/SHP-2 to the ITIM/ITSM domain in the PD-1 tail and increasing the expression of transcription factor BATF. In addition, PD-1 inhibitory signaling antagonizes positive T cell signaling events triggered by (1) TCR interacting with MHC and (2) CD28 interacting with CD80. (3) PD-1 signaling inhibits ZAP70 and the RAS-ERK and PI3K-AKT-mTOR signaling pathways. B Mechanisms of PD-1 signaling in macrophages. PD-1 inhibits macrophage function by recruiting phosphatases SHP-1/SHP-2 to the ITIM/ITSM domain in the PD-1 tail, leading to inhibition of the PI3K-NF-κB signaling pathway. Moreover, PD-1 signaling suppresses IFN-γ-activated M1 macrophage polarization by reducing the phosphorylation of STAT1 and the secretion of IL-12, while promoting IL-4-activated M2 macrophage polarization by increasing STAT6 phosphorylation. Red lines ending in a bar represent inhibitory signaling, and black arrows indicate positive signaling. Abbreviations: PD-1, programmed cell death protein 1; PD-L1/2, PD-1 ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC); ITIM, immunoreceptor tyrosine-based inhibitory motif; ITSM, immunoreceptor tyrosine-based switch motif; SHP, Src homology 2 domain-containing protein tyrosine phosphatase; BATF, basic leucine zipper ATF-like transcription factor; MHC, major histocompatibility complex; TCR, T cell receptor; CD, cluster of differentiation; ZAP70, zeta-chain-associated protein kinase 70; RAS, a small GTPase encoding RAS (retrovirus-associated DNA sequences); ERK, extracellular signal-regulated kinase; PI3K, type I phosphatidylinositol 3-kinase; AKT, serine/threonine-specific protein kinase; mTOR, mammalian target of rapamycin; PKC-θ, protein kinase C theta; NF-κB, nuclear factor kappa B; p-STAT1/6, phosphorylated signal transducer and activator of transcription 1/6; IL, interleukin; IFN-γ, interferon gamma; JAK, Janus kinase.