Post-transcriptional control of adaptive immunity and tumorigenesis

Coordinator : Manuel D. Diaz Munoz

Scientific objectives


Our immune system is essential for fighting infections and it can be trained to fight common viruses and pathogens, and to recognise and eliminate malignant cancer cells. Immune system function is shaped throughout vaccination and immunotherapy, two medical approaches that have revolutionized disease prevention and treatment for decades. Nonetheless, pathogen and cancer cell adaptation can limit the efficacy of these approaches making essential to understand further the genetic changes and mechanisms underlying lymphocyte development, activation and function.
Raising new knowledge on how genetic information encoded in our DNA controls all aspects of the immune response is the base of our research. Different layers of regulation, at the DNA, RNA and protein level, secure the correct expression of genes in immune cells. The interplay between these regulatory layers is complex, with messenger RNA (mRNA) acting as a bridge that controls immune cell function both in time and magnitude. mRNA molecules are decorated with RNA-binding proteins. These proteins control the nature of the nucleotide sequence as well as mRNA subcellular location, stability and translation into protein. Our research aims to understand how these RNA binding proteins control fundamental aspects in lymphocyte development and differentiation, and whether dynamic sensing of pathogens, cancer cells and other activated immune cells contribute to immune regulation.

Our projects


Axis 1. RNA-binding proteins in lymphocyte development & function.

Leading researcher: Manuel D. Diaz-Munoz


Development of a highly diversified immune system is essential to confer protection against ever-changing pathogens. Transcriptional and post-transcriptional gene regulatory networks must act coordinately for the generation of healthy lymphocytes in the thymus and the bone marrow. Our efforts aim to understand which is the contribution of RNA binding proteins in order to secure the correct development of lymphocytes, their selection and homeostatic maintenance.

With the help of transgenics mouse models and state-of-the art analysis of protein:RNA interactions, we explore how timely control of mechanisms such as mRNA splicing and translation allows the generation of lymphocytes with an expanded B- and T-cell receptor repertoire. Throughout the study of RNA binding proteins such as HuR and Tia1, we assess the pathological consequences of altering these post-transcriptional mechanisms in B and T lymphocytes, with a special emphasis on uncovering how they contribute to the launch of humoral and anti-tumoral responses.

Axis 2. Lymphocyte immunoregulation in germinal centres & humoral responses.

Leading researcher: Meryem Aloulou


Germinal centres (GCs) are central to the body’s defence against pathogens, and yet represent the origin of most non-Hodgkin B-cell lymphomas. These dynamic structures arise within secondary lymphoid organs, such as the spleen and lymph node, following infection. Within GCs, B cells undergo rapid clonal expansion and diversify their antibody repertoire, a process that relies on tightly coordinated interactions with T cells. Specialised T cell subsets, including T follicular helper (Tfh) and T follicular regulatory (Tfr) cells, critically shape the quality and durability of humoral immunity. Our research aims to uncover the role of CD8 Tregs, a poorly explored subset, and their intimate link with B cells in secondary lymphoid organs. We investigate how CD8 Tregs influence GC dynamics during responses to model antigens and infections, and how these regulatory interactions guide the development of robust or dysfunctional humoral immunity. Our work additionally considers how CD8 Tregs change with ageing. Their number and phenotypic profile shift across the lifespan, and these age-related changes may contribute to impaired GC function and weakened vaccine responses in older individuals. Thus, by integrating advanced transgenic mouse models with analyses of human samples, we dissect the complex cellular, molecular, post-transcriptional, and metabolic pathways that govern T-B cell communication. Through this approach, our research seeks to identify the mechanisms that underpin effective vaccination, maintain immune homeostasis, or drive pathological outcomes such as autoimmunity.

Axis 3. RNA- dependent regulation of mutagenic activity in normal and cancer B cells.

Leading researchers: Manuel D. Diaz-Munoz, Mailys Mouysset


Tight modulation of immunoglobulin (Ig) class-switch recombination, somatic hypermutation and DNA damage repair is essential for antibody production. However, miss-targeted mutations can lead to chromosomal translocation and B cell tumour transformation. The protein named Activation-Induced Deaminase (AID) is the main responsible for genome mutagenesis in GC B cells as well as in several B cell lymphomas. Thus, our main objective is to understand how AID and other RNA binding proteins enable Ig- class switch recombination and somatic hypermutation in B cells while preserving the genome integrity. Mutagenesis and DNA repair are highly regulated processes linked to B cell proliferation. The existence of different cell cycle checkpoints is essential for evaluation and depletion of B cells with extensive mutations. Our research is specialised focused on characterising the molecular mechanisms and signalling pathways that modulate protein and mRNA subcellular location as well as the translation of oncogenes in normal and cancer B cells. How RNA-binding proteins contribute to the selection of mutated GC B cells producing high-affinity antibodies while preventing B-cell tumour transformation is a major question yet to be answered.

Axis 4. Coupling antigen sensing and translational control in immunity & cancer.

Leading researcher: Virginie Mieulet


Our research is also aiming at understanding how antigen-dependent activation of MAPK signalling pathway triggers post-transcriptional networks that control lymphocyte activation, differentiation and functions. Our most recent studies indicate that MAPK activation acts as an alternative to mTOR signalling for setting the time and magnitude of expression of specific proteins in tumour-infiltrating lymphocytes (TILs). Thus, our studies aim to assess whether MAPK signalling enhances or restrains the cytotoxic activity of TILs to enhance tumour growth, by controlling the translation of specific mRNA targets. Our strategy integrates cutting-edge technologies (CITE-seq, Ribo-seq, multiplex imaging) with comprehensive analyses in relevant cellular models of cancer–experienced T cells, preclinical cancer models, and patient samples. The ultimate goal is to assess whether translational reprogramming in TILs affects anti-tumoral immunity and set the clinical relevance of inhibiting the translation machinery for cancer patients with MAPK alterations.

Other details


Our Team

Our team was established at INFINITY in 2018. We actively seek to support and recruit young and talented investigators that share our interests in Biomedical Research and Immunology. Informal enquiries will be considered for those wishing to join us. Please send your CV (max. three A4 pages including your scientific contributions) and a cover letter describing your interests by email. Funding options (studentships, fellowships and project-associated work contracts) will be discussed based on candidate’s merits and career expectations.

Main Publications

2025

Mailys Mouysset Dunja Capitan-Sobrino, Orlane Maloudi

Posttranscriptional control of the B cell receptor by HuR is essential for innate B cell maintenance and function Journal Article

In: Proceedings of the National Academy of Sciences (PNAS), vol. 122, no. 37, pp. e2421149122, 2025.

Abstract | Links | BibTeX

2024

Orlane Maloudi Ines C. Osma-Garcia, Mailys Mouysset; Diaz-Muñoz, Manuel D.

Post-transcriptional regulation by TIA1 and TIAL1 controls the transcriptional program enforcing T cell quiescence Journal Article

In: Biorxiv, 2024.

Abstract | Links | BibTeX

2023

Osma-Garcia, Ines C.; Mouysset, Mailys; Capitan-Sobrino, Dunja; Aubert, Yann; Turner, Martin; Diaz-Muñoz, Manuel D.

The RNA binding proteins TIA1 and TIAL1 promote Mcl1 mRNA translation to protect germinal center responses from apoptosis Journal Article

In: Cellular & Molecular Immunology, 2023, ISSN: 2042-0226.

Abstract | Links | BibTeX

2022

Matheson, Louise S.; Petkau, Georg; S'aenz-Narciso, Beatriz; D'Angeli, Vanessa; McHugh, Jessica; Newman, Rebecca; Munford, Haydn; West, James; Chakraborty, Krishnendu; Roberts, Jennie; Łukasiak, Sebastian; D'iaz-Muñoz, Manuel D.; Bell, Sarah E.; Dimeloe, Sarah; Turner, Martin

Multiomics analysis couples mRNA turnover and translational control of glutamine metabolism to the differentiation of the activated CD4+ T cell Journal Article

In: Scientific Reports, vol. 12, no. 1, pp. 19657, 2022, ISSN: 2045-2322.

Abstract | Links | BibTeX

Diaz-Munoz, M. D.; Osma-Garcia, I. C.

The RNA regulatory programs that govern lymphocyte development and function Journal Article

In: Wiley Interdiscip Rev RNA, vol. 13, no. 1, pp. e1683, 2022, ISSN: 1757-7012 (Electronic) 1757-7004 (Linking).

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Cacheiro-Llaguno, Cristina; Hernández-Subirá, Elena; Díaz-Muñoz, Manuel D.; Fresno, Manuel; Serrador, Juan M.; Íñiguez, Miguel A.

Regulation of Cyclooxygenase-2 Expression in Human T Cells by Glucocorticoid Receptor-Mediated Transrepression of Nuclear Factor of Activated T Cells Journal Article

In: International Journal of Molecular Sciences, vol. 23, no. 21, 2022, ISSN: 1422-0067.

Abstract | Links | BibTeX

Osma-Garcia, Ines C.; Capitan-Sobrino, Dunja; Mouysset, Mailys; Aubert, Yann; Maloudi, Orlane; Turner, Martin; Diaz-Muñoz, Manuel D.

The splicing regulators TIA1 and TIAL1 are required for the expression of the DNA damage repair machinery during B cell lymphopoiesis Journal Article

In: Cell Reports, vol. 41, no. 12, pp. 111869, 2022, ISSN: 2211-1247.

Abstract | Links | BibTeX

Hu, F.; Lu, J.; Matheson, L. S.; Diaz-Munoz, M. D.; Saveliev, A.; Turner, M.

Correction to: ORFLine: a bioinformatic pipeline to prioritize small open reading frames identifies candidate secreted small proteins from lymphocytes Journal Article

In: Bioinformatics, 2022, ISSN: 1367-4811 (Electronic) 1367-4803 (Linking).

Links | BibTeX

2021

Osma-Garcia, I. C.; Capitan-Sobrino, D.; Mouysset, M.; Bell, S. E.; Lebeurrier, M.; Turner, M.; Diaz-Munoz, M. D.

The RNA-binding protein HuR is required for maintenance of the germinal centre response Journal Article

In: Nat Commun, vol. 12, no. 1, pp. 6556, 2021, ISSN: 2041-1723 (Electronic) 2041-1723 (Linking).

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Mieulet, V.; Garnier, C.; Kieffer, Y.; Guilbert, T.; Nemati, F.; Marangoni, E.; Renault, G.; Chamming's, F.; Vincent-Salomon, A.; Mechta-Grigoriou, F.

Stiffness increases with myofibroblast content and collagen density in mesenchymal high grade serous ovarian cancer Journal Article

In: Sci Rep, vol. 11, no. 1, pp. 4219, 2021, ISSN: 2045-2322 (Electronic) 2045-2322 (Linking).

Links | BibTeX

Hu, F.; Lu, J.; Matheson, L. S.; Diaz-Munoz, M. D.; Saveliev, A.; Turner, M.

ORFLine: a bioinformatic pipeline to prioritise small open reading frames identifies candidate secreted small proteins from lymphocytes Journal Article

In: Bioinformatics, 2021, ISSN: 1367-4811 (Electronic) 1367-4803 (Linking).

Links | BibTeX

Boccasavia, V. L.; Bovolenta, E. R.; Villanueva, A.; Borroto, A.; Oeste, C. L.; van Santen, H. M.; Prieto, C.; Alonso-Lopez, D.; Diaz-Munoz, M. D.; Batista, F. D.; Alarcon, B.

Antigen presentation between T cells drives Th17 polarization under conditions of limiting antigen Journal Article

In: Cell Rep, vol. 34, no. 11, pp. 108861, 2021, ISSN: 2211-1247 (Electronic).

Links | BibTeX

Belot, A.; Gourbeyre, O.; Palin, A.; Rubio, A.; Largounez, A.; Besson-Fournier, C.; Latour, C.; Lorgouilloux, M.; Gallitz, I.; Montagner, A.; Polizzi, A.; Regnier, M.; Smati, S.; Zhang, A. S.; Diaz-Munoz, M. D.; Steinbicker, A. U.; Guillou, H.; Roth, M. P.; Coppin, H.; Meynard, D.

Endoplasmic reticulum stress controls iron metabolism through TMPRSS6 repression and hepcidin mRNA stabilization by RNA-binding protein HuR Journal Article

In: Haematologica, vol. 106, no. 4, pp. 1202-1206, 2021, ISSN: 1592-8721 (Electronic) 0390-6078 (Linking).

Links | BibTeX

2020

Lee, S.; Micalizzi, D.; Truesdell, S. S.; Bukhari, S. I. A.; Boukhali, M.; Lombardi-Story, J.; Kato, Y.; Choo, M. K.; Dey-Guha, I.; Ji, F.; Nicholson, B. T.; Myers, D. T.; Lee, D.; Mazzola, M. A.; Raheja, R.; Langenbucher, A.; Haradhvala, N. J.; Lawrence, M. S.; Gandhi, R.; Tiedje, C.; Diaz-Munoz, M. D.; Sweetser, D. A.; Sadreyev, R.; Sykes, D.; Haas, W.; Haber, D. A.; Maheswaran, S.; Vasudevan, S.

A post-transcriptional program of chemoresistance by AU-rich elements and TTP in quiescent leukemic cells Journal Article

In: Genome Biol, vol. 21, no. 1, pp. 33, 2020, ISSN: 1474-760X (Electronic) 1474-7596 (Linking).

Links | BibTeX

2019

Trulley, P.; Snieckute, G.; Bekker-Jensen, D.; Menon, M. B.; Freund, R.; Kotlyarov, A.; Olsen, J. V.; Diaz-Munoz, M. D.; Turner, M.; Bekker-Jensen, S.; Gaestel, M.; Tiedje, C.

Alternative Translation Initiation Generates a Functionally Distinct Isoform of the Stress-Activated Protein Kinase MK2 Journal Article

In: Cell Rep, vol. 27, no. 10, pp. 2859-2870 e6, 2019, ISSN: 2211-1247 (Electronic).

Links | BibTeX

Gentric, G.; Kieffer, Y.; Mieulet, V.; Goundiam, O.; Bonneau, C.; Nemati, F.; Hurbain, I.; Raposo, G.; Popova, T.; Stern, M. H.; Lallemand-Breitenbach, V.; Muller, S.; Caneque, T.; Rodriguez, R.; Vincent-Salomon, A.; de The, H.; Rossignol, R.; Mechta-Grigoriou, F.

PML-Regulated Mitochondrial Metabolism Enhances Chemosensitivity in Human Ovarian Cancers Journal Article

In: Cell Metab, vol. 29, no. 1, pp. 156-173 e10, 2019, ISSN: 1932-7420 (Electronic) 1550-4131 (Linking).

Links | BibTeX

2018

Diaz-Munoz, M. D.; Turner, M.

Uncovering the Role of RNA-Binding Proteins in Gene Expression in the Immune System Journal Article

In: Front Immunol, vol. 9, pp. 1094, 2018, ISSN: 1664-3224 (Print) 1664-3224 (Linking).

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Givel, A. M.; Kieffer, Y.; Scholer-Dahirel, A.; Sirven, P.; Cardon, M.; Pelon, F.; Magagna, I.; Gentric, G.; Costa, A.; Bonneau, C.; Mieulet, V.; Vincent-Salomon, A.; Mechta-Grigoriou, F.

miR200-regulated CXCL12beta promotes fibroblast heterogeneity and immunosuppression in ovarian cancers Journal Article

In: Nat Commun, vol. 9, no. 1, pp. 1056, 2018, ISSN: 2041-1723 (Electronic) 2041-1723 (Linking).

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Mendoza, P.; Martinez-Martin, N.; Bovolenta, E. R.; Reyes-Garau, D.; Hernansanz-Agustin, P.; Delgado, P.; Diaz-Munoz, M. D.; Oeste, C. L.; Fernandez-Pisonero, I.; Castellano, E.; Martinez-Ruiz, A.; Alonso-Lopez, D.; Santos, E.; Bustelo, X. R.; Kurosaki, T.; Alarcon, B.

R-Ras2 is required for germinal center formation to aid B cells during energetically demanding processes Journal Article

In: Sci Signal, vol. 11, no. 532, 2018, ISSN: 1937-9145 (Electronic) 1945-0877 (Linking).

Links | BibTeX

Monzon-Casanova, E.; Screen, M.; Diaz-Munoz, M. D.; Coulson, R. M. R.; Bell, S. E.; Lamers, G.; Solimena, M.; Smith, C. W. J.; Turner, M.

The RNA-binding protein PTBP1 is necessary for B cell selection in germinal centers Journal Article

In: Nat Immunol, vol. 19, no. 3, pp. 267-278, 2018, ISSN: 1529-2916 (Electronic) 1529-2908 (Linking).

Links | BibTeX

Turner, M.; Diaz-Munoz, M. D.

RNA-binding proteins control gene expression and cell fate in the immune system Journal Article

In: Nat Immunol, vol. 19, no. 2, pp. 120-129, 2018, ISSN: 1529-2916 (Electronic) 1529-2908 (Linking).

Links | BibTeX

2017

Diaz-Munoz, M. D.; Monzon-Casanova, E.; Turner, M.

Characterization of the B Cell Transcriptome Bound by RNA-Binding Proteins with iCLIP Journal Article

In: Methods Mol Biol, vol. 1623, pp. 159-179, 2017, ISSN: 1940-6029 (Electronic) 1064-3745 (Linking).

Links | BibTeX

Diaz-Munoz, M. D.; Kiselev, V. Y.; Le Novere, N.; Curk, T.; Ule, J.; Turner, M.

Tia1 dependent regulation of mRNA subcellular location and translation controls p53 expression in B cells Journal Article

In: Nat Commun, vol. 8, no. 1, pp. 530, 2017, ISSN: 2041-1723 (Electronic) 2041-1723 (Linking).

Links | BibTeX

2016

Tiedje, C.; Diaz-Munoz, M. D.; Trulley, P.; Ahlfors, H.; Laass, K.; Blackshear, P. J.; Turner, M.; Gaestel, M.

The RNA-binding protein TTP is a global post-transcriptional regulator of feedback control in inflammation Journal Article

In: Nucleic Acids Res, vol. 44, no. 15, pp. 7418-40, 2016, ISSN: 1362-4962 (Electronic) 0305-1048 (Linking).

Links | BibTeX

Galloway, A.; Saveliev, A.; Lukasiak, S.; Hodson, D. J.; Bolland, D.; Balmanno, K.; Ahlfors, H.; Monzon-Casanova, E.; Mannurita, S. C.; Bell, L. S.; Andrews, S.; Diaz-Munoz, M. D.; Cook, S. J.; Corcoran, A.; Turner, M.

RNA-binding proteins ZFP36L1 and ZFP36L2 promote cell quiescence Journal Article

In: Science, vol. 352, no. 6284, pp. 453-9, 2016, ISSN: 1095-9203 (Electronic) 0036-8075 (Linking).

Links | BibTeX

2015

Diaz-Munoz, M. D.; Bell, S. E.; Turner, M.

Deletion of AU-rich elements within the Bcl2 3'UTR reduces protein expression and B cell survival in vivo Journal Article

In: PLoS One, vol. 10, no. 2, pp. e0116899, 2015, ISSN: 1932-6203 (Electronic) 1932-6203 (Linking).

Links | BibTeX

Diaz-Munoz, M. D.; Bell, S. E.; Fairfax, K.; Monzon-Casanova, E.; Cunningham, A. F.; Gonzalez-Porta, M.; Andrews, S. R.; Bunik, V. I.; Zarnack, K.; Curk, T.; Heggermont, W. A.; Heymans, S.; Gibson, G. E.; Kontoyiannis, D. L.; Ule, J.; Turner, M.

The RNA-binding protein HuR is essential for the B cell antibody response Journal Article

In: Nat Immunol, vol. 16, no. 4, pp. 415-25, 2015, ISSN: 1529-2916 (Electronic) 1529-2908 (Linking).

Links | BibTeX

Main Funding

Major funding bodies:

Agence nationale de la recherche (ANR) (AAPG2020, 2022 and 2024)

Institut national du cancer (INCA) (PLBIO 2021 and 2024)

Inserm ITMO-Cancer (2024)

Fondation pour la Recherche Médicale (FRM Team 2023)

La Ligue contre le cancer (2020 – 2022)

Boehringer Ingelheim Fonds (2020-2023) 

ATIP-Avenir, Plan Cancer, CNRS and INSERM (2018-2022)

Media and Public Engagement

@diazmunoz-lab.bsky.social

twitter.com/DiazMunoz_Lab

Virginie Mieulet in Women in Science Week

 

Partenaires Equipe 2

Programme ATIP - Avenir

Programme ATIP - Avenir

Plan cancer 2014-2019

Plan cancer 2014-2019

CNRS

CNRS

ANR

ANR

L'INCA cancer

L'INCA cancer

Boehringer Ingelheim Fonds

Boehringer Ingelheim Fonds