Opposing regulatory functions of the TIM3 (HAVCR2) signalosome in primary effector T cells as revealed by quantitative interactomics

Yunhao Zhai (1) , Javier Celis-Gutierrez (2) , Guillaume Voisinne (1) , Daiki Mori (1) , Laura Girard (1) , Odile Burlet-Schiltz (3) , Anne Gonzalez de Peredo (3) , Romain Roncagalli (1) , Bernard Malissen (1)

1 CIML - Centre d'Immunologie de Marseille - Luminy
2 CRCM - Centre de Recherche en Cancérologie de Marseille
3 IPBS - Institut de pharmacologie et de biologie structurale

Deciphering how T-cell antigen receptor signals are modulated by coinhibitors is a fundamental goal in immunology and of considerable clinical interest because blocking coinhibitory signals via therapeutic antibodies have become a standard cancer immunotherapeutic strategy. Most of the attention devoted to T-cell immunoglobulin and mucin domain-3 (TIM3; also known as HAVCR2 or CD366) molecules stems from their expression on exhausted T cells in settings of chronic viral infection and tumors. Moreover, T cells expressing high levels of both PD-1 and TIM3 coinhibitors appear more dysfunctional than those expressing PD-1 alone. Combination therapies intending to block both PD-1 and TIM3 are thus actively being explored in the cancer treatment setting. Upon interaction with Galectin-9 (GAL-9) and carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM-1), the tyrosines found in the TIM3 cytoplasmic tail are phosphorylated.1 Because these conserved tyrosines do not form a recognizable inhibitory signaling motif, the mechanism by which TIM3 transmits inhibitory signals has not been elucidated. Paradoxically, TIM3 also has costimulatory activity in T cells.2,3 Published biochemical studies attempting to unveil the mode of action of TIM3 have relied on approaches addressing one candidate effector at a time with limited quantitative insight, and most used transformed cells. Using mice expressing an affinity Twin-Strep-tag (OST) at the TIM3-protein C-terminus (TIM3OST mice) (Figs. 1a and S1a) and affinity purification coupled with mass spectrometry (AP-MS), we herein defined the composition and dynamics of the signaling protein complex (signalosome) used by TIM3 in primary effector T cells. These results provide a more complete model of TIM3 signaling and explain its paradoxical coinhibitory and costimulatory functions

Mots clés: Adaptive immunity; Signal transduction

Domaines: Immunologie

Yunhao Zhai, Javier Celis-Gutierrez, Guillaume Voisinne, Daiki Mori, Laura Girard, et al.. Opposing regulatory functions of the TIM3 (HAVCR2) signalosome in primary effector T cells as revealed by quantitative interactomics. Cellular and molecular immunology, In press, ⟨10.1038/s41423-020-00575-7⟩. ⟨hal-03086942⟩