Summary: Deciphering how TCR signals are modulated by coinhibitory receptors is of fundamental and clinical interest. Using quantitative interactomics, we define the composition and dynamics of the PD-1 and BTLA coinhibitory signalosomes in primary effector T cells and at the T cell-antigen-presenting cell interface. We also solve the existing controversy regarding the role of the SHP-1 and SHP-2 protein-tyrosine phosphatases in mediating PD-1 coinhibition. PD-1 predominantly recruits SHP-2, but when absent, it recruits SHP-1 and remains functional. In contrast, BTLA predominantly recruits SHP-1 and to a lesser extent SHP-2. By separately analyzing the PD-1-SHP-1 and PD-1-SHP-2 complexes, we show that both dampen the TCR and CD28 signaling pathways equally. Therefore, our study illustrates how comparison of coinhibitory receptor signaling via quantitative interactomics in primary T cells unveils their extent of redundancy and provides a rationale for designing combinations of blocking antibodies in cancer immunotherapy on the basis of undisputed modes of action. : The respective contributions of the SHP-1 and SHP-2 protein-tyrosine phosphatases to PD-1 coinhibition remain debated. Using quantitative interactomics, Celis-Gutierrez et al. define the composition of the PD-1 signalosomes in primary T cells. Deconstructing it into PD-1-SHP-2 and PD-1-SHP-1 complexes showed that they target the TCR and CD28 pathways equally. Keywords: T cell, coinhibitory receptors, PD-1, BTLA, protein tyrosine phosphatases, SHP-1, SHP-2, cancer immunotherapy, combination therapy design, quantitative interactomics
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