Fig. 2

Immune checkpoint downstream inhibitory signaling in CD8⁺ T cells. Immune checkpoint pathways initiated after binding of ligands to their respective IC receptors (blue boxes) interfere with TCR signaling by a variety of mechanisms. ICs have inhibitory motifs in their cytoplasmic tail that can recruit (blue arrows) protein tyrosine phosphatases SHP1 and/or SHP2, which are responsible for dephosphorylating (red inhibitory arrows) TCR downstream signaling proteins. This is the case for PVRIG, 2B4, Siglec-7/−9, ILT2, BTLA, KIR-L, NKG2A, TIGIT, PD-1, and KLRG1. However, some ICs, such as CTLA-4, TIM-3, CD47, and CD200R1, present alternative downstream mechanisms, while other IC downstream signaling, such as that involving LAG-3, VISTA, CD96, CD160, and B7-H3, remains to be fully elucidated. Schematic representation of (A) SHP1-dependent inhibition of TCR signaling, (B) SHP2-dependent inhibition of TCR signaling, and (C) non-dependent SHP1 and SHP2 inhibition of TCR signaling. Dotted lines indicate indirect mechanisms (created with BioRender.com)