Dr. Bernard Malissen - Multi-omics dissection of T cell-dendritic cell interactions helps designing targeted immunotherapies - IPBS-Toulouse, Hybrid Seminar (Seminar Room)

Bernard Malissen

Centre d’Immunologie de Marseille-Luminy (CIML) and Centre d’Immunophénomique (CIPHE), Aix Marseille Université, INSERM, CNRS, 13288 Marseille, France

T cells play a central role in adaptive immunity. Although the T cell antigen receptor (TCR) controls T cell physiology, it does not work in isolation and the signals it triggers are tuned by a multitude of other surface receptors that deliver positive (costimulators) and negative (coinhibitors) informations about the state of activation of antigen-presenting cells (primarily dendritic cells). Therapeutic antibodies (immune-checkpoint inhibitors) blocking coinhibitors have become standard treatment for metastatic melanoma, leading to a revival in the study of T cell coinhibition and costimulation. However, we lack a satisfying comprehension of the way T cells integrate inputs from multiple signalling pathways and use inter-pathway crosstalk to make informed decisions. To make sense of the formidable complexity of the signal transduction networks involved in T cell activation and the role played by the different types of dendritic cells in T cell activation, we combined “omic” and mouse genetics. It allowed us to decipher in a time-resolved and quantitative manner the dynamics of the protein signaling complexes (signalosomes) that assemble in primary T cells following physiologic TCR engagement. To further illustrate the interest of multi-omics approaches, I will present recent data demonstrating how corrupted LAT signalosomes lead to an inflammatory and autoimmune disease recapitulating human IgG4-related disease. Novel data will be also presented revealing that, although humans and mice have evolved independently for over 90 million years, their TCR-signaling network has an unexpected high degree of qualitative and quantitative conservation.

References

• Celis-Gutierrez, J., Blattmann, P., Zhai, Y., Jarmuzynski, N., Ruminski, K., Gregoire, C., Ounoughene, Y., Fiore, F., Aebersold, R., Roncagalli, R., et al. (2019). Quantitative Interactomics in Primary T Cells Provides a Rationale for Concomitant PD-1 and BTLA Coinhibitor Blockade in Cancer Immunotherapy. Cell Rep 27, 3315-3330 e3317.
• Mori, D., Gregoire, C., Voisinne, G., Celis-Gutierrez, J., Aussel, R., Girard, L., Camus, M., Marcellin, M., Argenty, J., Burlet-Schiltz, O., et al. (2021). The T cell CD6 receptor operates a multitask signalosome with opposite functions in T cell activation. J Exp Med 218.
• Voisinne, G., Kersse, K., Chaoui, K., Lu, L., Chaix, J., Zhang, L., Goncalves Menoita, M., Girard, L., Ounoughene, Y., Wang, H., et al. (2019). Quantitative interactomics in primary T cells unveils TCR signal diversification extent and dynamics. Nat Immunol 20, 1530-1541.
• Wohn, C., Le Guen, V., Voluzan, O., Fiore, F., Henri, S., and Malissen, B. (2020). Absence of MHC class II on cDC1 dendritic cells triggers fatal autoimmunity to a cross-presented self-antigen. Sci Immunol 5.
• Zhai, Y., Celis-Gutierrez, J., Voisinne, G., Mori, D., Girard, L., Burlet-Schiltz, O., de Peredo, A.G., Roncagalli, R., and Malissen, B. (2021). Opposing regulatory functions of the TIM3 (HAVCR2) signalosome in primary effector T cells as revealed by quantitative interactomics. Cell Mol Immunol 18, 1581-1583.