U-1160 Team 2 “Thymic function and development” (A. Toubert, K. Benlagha)

 Team leader:  TOUBERT Antoine (PUPH, U. Paris, APHP)

 

 Deputy team leader: BENLAGHA Kamel (DR2 INSERM, HDR)

 

Composition

TOUBERT Antoine (PUPH, U. Paris, APHP)

BENLAGHA Kamel (DR2 INSERM, HDR)

CLAVE Emmanuel (IR, U. Paris)

KERGARAVAT Camille (IE, U. Paris)

AMABLE Ludivine (Doctorante, U. Paris)

 

Main topic:

Scientific interests of this team focus on basic and translational aspects of thymopoiesis, combining murine models of T-cell development and human studies.  

The group of K. Benlagha developed a deep expertise in the study of invariant NKT cells (iNKT) in murine models and in humans. He described the iNKT17 subset with a specific focus on the development of this subset compared to iNKT1 and iNKT2.
The group of A. Toubert developed interest in T-cell repertoire and thymic function analysis in human immunology and immunopathology (autoimmunity, T-cell reconstitution after hematopoietic stem cell transplantation). He developed molecular markers of T and B cell immune competence based on the physiological processes of DNA rearrangements (“excision circles”) during lymphocyte differentiation, namely sj and b T cell Receptor Excision Circle (TREC) as surrogate markers of thymic function and K-chain rearrangement excision circle (KREC) for B-cell lymphogenesis.

 

Scientific strategy:

Human thymic function: deciphering a genetic control at the TCRA/D locus.

Graphical abstract of human thymopoïesis

We have shown in a population immunology approach with genome-wide association studies in 2 independent cohorts that age, gender and a single-nucleotide polymorphism (SNP) within the TCRA/D region (rs2204985 A/G) can influence the level of thymopoiesis. This translates in about 40% increase in thymopoiesis estimated by TRECs amounts in GG vs. AA homozygotes, the effect of this genetic polymorphism being independent of age  (Clave et al, Sci Transl Med 2018).

Projects combine ex vivo (human thymic samples), in vitro (artificial thymic organoids) and in vivo approaches (human immune system or HIS mice).  

Human thymic function in aging and regenerative strategies, especially RANKL (ANR project “RANKL-Thym”).
Trafficking and development in healthy human thymus (coll. Teams 1 and 3).
Thymic development of iNKT subsets in normal and mutant mice.

Current research of K. Benlagha’s group focuses on how thymic NKT cells differentiate into different functional subsets in mice and in the human thymus.

 

Selected publications (2018-2020)

1 - Cortical Thymocytes Along With Their Selecting Ligands Are Required for the Further Thymic Maturation of NKT Cells in Mice. Klibi J, Benlagha K. Front Immunol. 2020 May 7;11:815.

2 - A focus on natural killer T-cell subset characterization and developmental stages. Klibi J, Amable L, Benlagha K. Immunol Cell Biol. 2020 May;98(5):358-368. Review.

3- Characterization of the developmental landscape of murine RORγt+ iNKT cells.

Klibi J, Li S, Amable L, Joseph C, Brunet S, Delord M, Parietti V, Jaubert J, Marie J, Karray S, Eberl G, Lucas B, Toubert A, Benlagha K.

Int Immunol. 2020 Feb 7;32(2):105-116.

4 - Accelerated thymopoiesis and improved T-cell responses in HLA-A2/-DR2 transgenic BRGS-based human immune system mice.

Masse-Ranson G, Dusséaux M, Fiquet O, Darche S, Boussand M, Li Y, Lopez-Lastra S, Legrand N, Corcuff E, Toubert A, Centlivre M, Bruel T, Spits H, Schwartz O, Lévy Y, Strick-Marchand H, Di Santo JP.

Eur J Immunol. 2019 Jun;49(6):954-965.

5 - TCR density in early iNKT cell precursors regulates agonist selection and subset differentiation in mice.

Joseph C, Klibi J, Amable L, Comba L, Cascioferro A, Delord M, Parietti V, Lenoir C, Latour S, Lucas B, Viret C, Toubert A, Benlagha K.

Eur J Immunol. 2019 Jun;49(6):894-910.

6 - Human thymopoiesis is influenced by a common genetic variant within the TCRA-TCRD locus.

*Clave E, *Araujo IL, *Alanio C, *Patin E, *Bergstedt J, Urrutia A, Lopez-Lastra S, Li Y, Charbit B, MacPherson CR, Hasan M, Melo-Lima BL, Douay C, Saut N, Germain M, Trégouët DA, Morange PE, Fontes M, Duffy D, Di Santo JP, Quintana-Murci L, Albert ML, Toubert A; Milieu Intérieur Consortium. (* co-authors).

Sci Transl Med. 2018 Sep 5;10(457-468).

Press release from INSERM, I. Pasteur and U. Paris. Highlighted by F1000.

7 - A human immune system mouse model with robust lymph node development.

Li Y, Masse-Ranson G, Garcia Z, Bruel T, Kök A, Strick-Marchand H, Jouvion G, Serafini N, Lim AI, Dusseaux M, Hieu T, Bourgade F, Toubert A, Finke D, Schwartz O, Bousso P, Mouquet H, Di Santo JP.

Nat Methods. 2018 Aug;15(8):623-630. 

8 - Hematopoietic Stem Cell Transplantation in its 60s : a platform for cellular therapies.

Chabannon C, Kuball J, Bondanza A, Dazzi F, Pedrazzoli P, Toubert A, Ruggeri A, Fleischhauer K, Bonini C, on behalf of the EBMT Cell Therapy and Immunobiology Working Party (CTIWP)

Sci Transl Med. 2018 Apr 11;10(436). Review.

9 - Immune rebound associates with a favorable clinical response to autologous HSCT in systemic sclerosis patients.

Arruda LCM, Malmegrim KCR, Lima-Júnior JR, Clave E, Dias JBE, Moraes DA, Douay C, Fournier I, Moins-Teisserenc H, Alberdi AJ, Covas DT, Simões BP, Lansiaux P, *Toubert A, *Oliveira MC. (* co-authors)

Blood Adv. 2018 Jan 23;2(2):126-141. 

10 -  Naïve CD8+ T-Cells Engage a Versatile Metabolic Program Upon Activation in Humans and Differ Energetically From Memory CD8+ T-Cells.

Nicoli F, Papagno L, Frere JJ, Cabral-Piccin MP, Clave E, Gostick E, Toubert A, Price DA, Caputo A, Appay V.

Front Immunol. 2018 Dec 21;9:2736.

 

Major grants during the 2015-2020 period

ANR PRC 2014 « PriCelAge »

ANR PRC 2019 “RANKL-Thym”

PRT-K INCa/DGOS 2017 BM-Immune-MDS

Labex « Milieu Intérieur » (2020-2025), partner and member of the scientific board (http://www.milieuinterieur.fr/en/)

 

Main networks and collaborations

Institut Hospitalo-Universitaire (IHU) THEMA “The European Leukemia Institute”

Institut Carnot OPALE, the Organization for Partnerships in Leukemia

Recherche Hospitalo-Universitaire en Santé (RHU) 2018 « IRIS » (coord. M. Cavazzana, IMAGINE): la thérapie génique des maladies héréditaires monogéniques du système immunitaire

International collaborations:  FOCIS international center of excellence), COST (EC CA17138) “EUROGRAFT”.

 

Alumni

S. GLAUZY PhD (2010-2014)

I. LESTON ARAUJO PhD, bursary from CAPES (Brazil) “Science out of borders” (2104-2019). Received the 2019 Jon van Rood award of the European Society for Blood and Marrow Transplantation (EBMT) (www.ebmt.org/ebmt/news/awards-ebmt-2019) 

L. ARRUDA PhD, FAPESP bursary from FAPESP (Brazil) (2014-2016)

B. MELO-LIMA, post-doc Labex Milieu Intérieur (2016-2018)

D. AL DULAMI PhD (2015-2018)

C. JOSEPH PhD (2013-2017)

S. LI PhD (2012-2016)

J. KLIBI, post-doc (2017-2019)