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Post-transcriptional gene regulation in lymphocyte homeostasis and disease

; Inserm

Interested in the complex interplay between transcriptional and post-transcriptional networks in immune cell biology, I first focused my studies on understanding how inflammation shapes innate responses in the laboratory of Prof. Manuel Fresno at the Center for Molecular Biology “Severo Ochoa” (CBMSO, Madrid, Spain). Then, I moved to the laboratory of Dr. Martin Turner at The 99�Ⱦò������µ�ַ (Cambridge, UK) to study how RNA binding proteins shape adaptive immune responses, making seed-grounding discoveries linking regulation of mRNA splicing and metabolic B cell activation. In 2018, I opened my lab at INFINITy (Toulouse, France) and, since then, we make use of genetics tools and molecular methodologies to study protein:RNA interactions and their contribution to the formation and maintenance of the lymphoid cell compartment and their implication in innate and adaptive immunity. Some recent discoveries in the lab highlight the importance of RNA binding proteins in launching the genetic programs for DNA damage repair in developing lymphocytes and quiescence in long-lasting peripheral mature lymphocytes. RNA binding proteins also support T-cell transcriptomic rewiring upon TCR activation and are required for the establishment of germinal centre responses. In the future, we look into a better characterization of the protein:RNA networks taking place in activated lymphocytes and how their deregulation impacts antigen-mediated immunity as well as pathogenic settings such as cancer.

Immune protection against infection relies on the quiescence maintenance of a highly diversified T-cell repertoire. Transcriptional networks cooperate to enforce T-cell quiescence. However, less is known about the post-transcriptional networks that preserve T-cell diversity. Our studies show that the RNA binding proteins TIA1 and TIAL1 act redundantly to maintain CD4 and CD8 T cells in the periphery. In their absence, T cells undergo uncontrolled cell proliferation, and premature T-cell activation, exhaustion and death. Mechanistically, TIA1 and TIAL1 preserve the expression of the master transcription factors FOXP1, LEF1 and TCF1 that enforce T-cell quiescence and block premature activation. During activation, TIA1 and TIAL1 control the expression of MYC to allow metabolic and functional reprogramming for launching T-cell mediated immune responses. In the germinal centre, TIA1 and TIAL1 take part in an RNA binding protein network that promotes formation of protein:RNA condensates for, possibly, regulating the dynamics of mRNA translation. Taken together, our studies highlight a previously unrecognized dependency on post-transcriptional gene regulation to enforce lymphocyte quiescence and activation upon antigen encounter.