Immune Checkpoint Receptors Signaling in T Cells

Abstract

The characterization of the receptors negatively modulating lymphocyte function is rapidly advancing, driven by success in tumor immunotherapy. As a result, the number of immune checkpoint receptors characterized from a functional perspective and targeted by innovative drugs continues to expand. This review focuses on the less explored area of the signaling mechanisms of these receptors, of those expressed in T cells. Studies conducted mainly on PD-1, CTLA-4, and BTLA have evidenced that the extracellular parts of some of the receptors act as decoy receptors for activating ligands, but in all instances, the tyrosine phosphorylation of their cytoplasmatic tail drives a crucial inhibitory signal. This negative signal is mediated by a few key signal transducers, such as tyrosine phosphatase, inositol phosphatase, and diacylglycerol kinase, which allows them to counteract TCR-mediated activation. The characterization of these signaling pathways is of great interest in the development of therapies for counteracting tumor-infiltrating lymphocyte exhaustion/anergy independently from the receptors involved.

Keywords: DGK; ITIM; ITSM; PDL-1; SHIP; SHP-1; SHP-2; SLAM; Src.

Figure 1

Balance of positive and negative signals tuning the immune response. Images created using RCSB PDB (www.rcsb.org accessed on 1 February 2022) and the Mol* application [10]. The TCR complex structure is 6JXR [11], the CTLA-4 partial dimeric structure is 3OSK [12], the ZAP70 structure is 4K2R [13], the SHP-2 structure is 2SHP [14], the SHIP-1 partial structure is 6XY7, the PD-1 extracellular domain is 3RRQ, and the CD28 extracellular is 6O8D (available in PDB, to be published). LCK, PLCΥ1, and DGKA models are from AlphaFold [15].

Figure 2

PD-1 structural features. PD-1 (288 aa) features from the Uniprot database; the extracellular domain in complex with its ligand PD-L1 (gray) is 4ZQK [37], rendered by the Mol* application [10].

Figure 3

CTLA-4 structural features. CTLA-4 (233 aa) features from the Uniprot database; the Ig-like V domain unbound dimeric structure (one subunit in gray with MYPPPY ligand binding evidenced in red) is 3OSK [12], rendered by the Mol* application [10].

Figure 4

BTLA structural features. BTLA (289 aa) features from the Uniprot database; the ectodomain in complex with HVEM (gray) is 2AW2 [66], rendered by the Mol* application [10].

Figure 5

SHP-2 structure. Structure of human SHP-2 lacking the C-terminal tail (66 ammino acid). This closed conformation presents the N-terminal SH2 (yellow), C-terminal SH2 (orange), and the catalytic domain (red). Image created using RCSB PDB (www.rcsb.org accessed on 1 February 2022) and the Mol* application (8) with 2SHP [14].

Figure 6

Model of DGKα. Model of DGKα structure from AlphaFold [15] rendered with the Mol* application [10] to show the two calcium binding EF hands (yellow), the two C1 domains (orange), and the split catalytic domain (red).