RIKEN Center for Integrative Medical Sciences Laboratory for Immune Crosstalk

Team Leader: Hilde Cheroutre (Ph.D.)

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Research Summary

Our research is focused on understanding and elucidating mechanisms of immune protection and regulation, which operate at the mucosal barrier of the intestine. We recently found that CD4 T cells harbor an unexpected degree of plasticity where mature CD4 T helper (Th) cells upon repeated antigenic stimulation under non-immunogenic conditions, are able to terminate the expression of the Th transcription factor, ThPOK, and gradually "reprogram" to MHC class II restricted CD4 cytotoxic T lymphocytes (CD4+CTL). At steady state, CD4+ CTL remain quiescent however under challenging conditions, these cells can become potent killer cells. Moreover, defects in the "reprogramming" process lead to the generation of pathogenic effector cells or excessive suppressive cells which respectively induce inflammatory diseases or impede on the protective capacity of the immune system to defeat not only pathogens but also tumor cells. Overall, based on the insights we are gaining from our research, a clear picture emerges which indicates that the mucosal immune defense adapts to the local environment and specializes to provide the most efficient and immediate protection in the face of preserving the integrity of the most critical mucosal barrier of the body. Using large data base approaches, we are currently dissecting the mechanisms and identify the network of factors which drive the reprogramming and control the function of CD4 CTL in mucosal-, antiviral-, and anti-tumor immunity as well as in autoimmunity. The discovery of LncRNAs as a novel layer of control over the functional fate of CD4 T cells has opened up a whole new field of research and new opportunities for medical intervention strategies.
In another study, we are aiming to understand the fate decisions and functional imprinting mediated during thymic development and self-antigen-based selection and the consequences this has on autoimmunity and immune anti-tumor surveillance (pathogenic and beneficial self-based immunity).

Main Research Fields

Biology

Related Research Fields

Medicine, Dentistry & Pharmacy

Keywords

Immune system
autoimmunity
vaccine
anti-cancer therapy
inflammatory diseases

Selected Publications

Papers with an asterisk(*) are based on research conducted outside of RIKEN.

1.Krause P, Morris V, Greenbaum JA, Park Y, Bjoerheden U, Mikulski Z, Muffley T, Shui JW, Kim G, Cheroutre H, Liu YC, Peters B, Kronenberg M, Murai M.:
“IL-10-producing intestinal macrophages prevent excessive antibacterial innate immunity by limiting IL-23 synthesis.”
Nat Commun, 6:7055. (2015)
2.Vicente-Suarez I, Larange A, Reardon C, Matho M, Feau S, Chodaczek G, Park Y, Obata Y, Gold R, Wang-Zhu Y, Lena C, Zajonc DM, Schoenberger SP, Kronenberg M,Cheroutre H.:
“Unique lamina propria stromal cells imprint the functional phenotype of mucosal dendritic cells.”
Mucosal Immunol, 8(1):141-51. (2015)
3.Mayans S, Stepniak D, Palida SF, Larange A, Dreux J, Arlian BM, Shinnakasu R, Kronenberg M, Cheroutre H, Lambolez F.:
“αβT cell receptors expressed by CD4(-)CD8αβ(-) intraepithelial T cells drive their fate into a unique lineage with unusual MHC reactivities.”
Immunity, 41(2):207-18. (2014)
4.*Davani D, Pancer Z, Cheroutre H, Ratcliffe MJ.:
“Negative selection of self-reactive chicken B cells requires B cell receptor signaling and is independent of the bursal microenvironment.”
J Immunol,192(7):3207-17. (2014)
5.Fu G, Casas J, Rigaud S, Rybakin V, Lambolez F, Brzostek J, Hoerter JA, Paster W, Acuto O, Cheroutre H, Sauer K, Gascoigne NR.:
“Themis sets the signal threshold for positive and negative selection in T-cell development.”
Nature, 504(7480):441-5. (2013)
6.Mucida D, Husain MM, Muroi S, van Wijk F, Shinnakasu R, Naoe Y, Reis BS, Huang Y, Lambolez F, Docherty M, Attinger A, Shui JW, Kim G, Lena CJ, Sakaguchi S, Miyamoto C, Wang P, Atarashi K, Park Y, Nakayama T, Honda K, Ellmeier W, Kronenberg M, Taniuchi I, Cheroutre H.:
“Transcriptional reprogramming of mature CD4⁺ helper T cells generates distinct MHC class II-restricted cytotoxic T lymphocytes.”
Nat Immunol, 14(3):281-9. (2013)
7.Grivennikov SI, Wang K, Mucida D, Stewart CA, Schnabl B, Jauch D, Taniguchi K, Yu GY, Osterreicher CH, Hung KE, Datz C, Feng Y, Fearon ER, Oukka M, Tessarollo L, Coppola V, Yarovinsky F, Cheroutre H, Eckmann L, Trinchieri G, Karin M.:
“Adenoma-linked barrier defects and microbial products drive IL-23/IL-17-mediated tumour growth.”
Nature, 491(7423):254-8. (2012)
8.Shui JW, Larange A, Kim G, Vela JL, Zahner S, Cheroutre H, Kronenberg M.:
“HVEM signalling at mucosal barriers provides host defence against pathogenic bacteria.”
Nature, 488(7410):222-5. (2012)
9.Huang Y, Park Y, Wang-Zhu Y, Larange A, Arens R, Bernardo I, Olivares-Villagómez D, Herndler-Brandstetter D, Abraham N, Grubeck-Loebenstein B, Schoenberger SP, Van Kaer L, Kronenberg M, Teitell MA, Cheroutre H.:
“Mucosal memory CD8⁺ T cells are selected in the periphery by an MHC class I molecule.”
Nat Immunol, Nat Immunol. (2011)
10.Mucida D, Park Y, Kim G, Turovskaya O, Scott I, Kronenberg M, Cheroutre H.:
“Reciprocal TH17 and regulatory T cell differentiation mediated by retinoic acid.”
Science, 317(5835):256-60. (2007)

Lab Members

Principal investigator

Hilde Cheroutre: Team Leader

Contact Information

5F, North Research Building,
1-7-22 Suehiro-cho, Tsurumi-ku,
Yokohama City, Kanagawa,
230-0045, Japan
Tel: +81-(0)45-503-7045
Fax: +81-(0)45-503-7043