Characterization of autoreactive T cells in the pathogenesis of Type I diabetes

Responsable du Stage : Dr. Zhicheng ZHOU

Tél : 33-1-76.53.55.83  E-mail:  zhicheng.zhou@inserm.fr…

Inserm U1016 – CNRS UMR8104 – Université de Paris

Résumé du Projet de Stage 

The autoimmune T cells infiltrating pancreatic islets eventually destroy insulin-secreting beta cells in type 1 diabetes (T1D). However, how T cells initiate T1D remains poorly understood. Our lab, led by Pr. Mallone and Dr. You, affiliated to the Diabetology Department of the Cochin Hospital, recently identified a first set of molecules over-expressed in these rare T-cell subsets of T1D patients. The M2 candidate will work on the identification and deconvolution of these molecules using cutting-edged single-cell RNAseq/TCRseq, systems biology and multiparametric flow cytometry and cell sorting. Specific features of the TCR repertoire will also be investigated through re-expression of relevant TCRs into carrier cells and definition of their antigenic reactivity. These data will help to understand how autoreactive T lymphocytes are involved in different stages of T1D pathogenesis in human, to select potential biomarkers for early stage diagnosis and, eventually, to develop immunotherapies targeting autoreactive T cells.

Profile of candidates (required but not exiged)

–  Immunology: strong motivation for immunology research, in particular adaptive T-cell immunity

– Systems biology: strong motivation for multiomics approaches (proteomics, transcriptomics, epigenetics), gene editing (CRISPR, gene transfer)

–  Bioinformatics: basis of R/Python/SQL

–  Molecular Biology: motivated for cloning, vector design, and associated software expertise

– Cellular Biology: motivated for cell culture (lines and primary cells), generation and stabilization of cell lines, optical and immunofluoresence microscopy

Dernières Publications en lien avec le projet :

1- Quiniou V, Barennes P, Mhanna V, Stys P, Vantomme H, Zhou Z, Martina F, Coatnoan N, Barbié-Sastre M, Pham HP, Clemenceau B, Vié H, Shugay M, Six A, Brandao B, Mallone R, Mariotti-Ferrandiz E, Klatzmann D. Human thymopoiesis produces polyspecific CD8+ α/β T cells responding to multiple viral antigens. Biorxiv https://doi.org/10.1101/2020.07.27.223354

2- Azoury ME, Samassa F, Buitinga M, Nigi L, Brusco N, Callebaut A, Giraud M, Irla M, Lalanne AI, Carré A, Afonso G, Zhou Z, Brandao B, Colli ML, Sebastiani G, Dotta F, Nakayama M, Eizirik DL, You S, Pinto S, Mamula MJ, Verdier Y, Vinh J, Buus S, Mathieu C, Overbergh L, Mallone R. CD8+ T Cells Variably Recognize Native Versus Citrullinated GRP78 Epitopes in Type 1 Diabetes. Diabetes 2021;70:2879-2891.

3- Carré A, Richardson SJ, Larger E, Mallone R. Presumption of guilt for T cells in type 1 diabetes: lead culprits or partners in crime depending on age of onset? Diabetologia 2021;64:15-25.

4- Mann S, Zhou Z, Landry LG, Anderson AM, Alkanani AK, Fischer J, Peakman M, Mallone R, Campbell K, Michels AW, Nakayama M. Multiplex T Cell Stimulation Assay Utilizing a T Cell Activation Reporter-Based Detection System. Front Immunol 2020; 11:633.

5- Azoury ME, Tarayrah M, Afonso G, Pais A, Colli ML, Maillard C, Lavaud C, Alexandre-Heymann L, Gonzalez-Duque S, Verdier Y, Vinh J, Pinto S, Buus S, Dubois-Laforgue D, Larger E, Beressi JP, Bruno G, Eizirik DL, You S, Mallone R. Peptides Derived From Insulin Granule Proteins Are Targeted by CD8+ T Cells Across MHC Class I Restrictions in Humans and NOD Mice. Diabetes 2020;69:2678-2690.

6- Culina S, Lalanne AI, Afonso G, Cerosaletti K, Pinto S, Sebastiani G, Kuranda K, Nigi L, Eugster A, Osterbye T, Maugein A, McLaren JE, Ladell K, Larger E, Beressi JP, Lissina A, Appay V, Davidson HW, Buus S, Price DA, Kuhn M, Bonifacio E, Battaglia M, Caillat-Zucman S, Dotta F, Scharfmann R, Kyewski B, Mallone R, ImMaDiab Study G. Islet-reactive CD8+ T cell frequencies in the pancreas, but not in blood, distinguish type 1 diabetic patients from healthy donors. Sci Immunol 2018;3:eaao4013.

7- Gonzalez-Duque S, Azoury ME, Colli ML, Afonso G, Turatsinze JV, Nigi L, Lalanne AI, Sebastiani G, Carre A, Pinto S, Culina S, Corcos N, Bugliani M, Marchetti P, Armanet M, Diedisheim M, Kyewski B, Steinmetz LM, Buus S, You S, Dubois-Laforgue D, Larger E, Beressi JP, Bruno G, Dotta F, Scharfmann R, Eizirik DL, Verdier Y, Vinh J, Mallone R. Conventional and Neo-antigenic Peptides Presented by beta Cells Are Targeted by Circulating Naive CD8+ T Cells in Type 1 Diabetic and Healthy Donors. Cell Metab 2018;28:946-960.


Ce projet s’inscrit-il dans la perspective d’une thèse :

                                                   oui x

si oui type de financement prévu :  Bourse Ecole-Doctorale, FRM ou Bourse IDF

 Ecole Doctorale de rattachement :  BioSPC

 

Intitulé de l’Unité : Inserm U1016 – CNRS UMR8104 – Université de Paris

Intitulé de l’équipe : Tolérance, biomarqueurs et thérapies dans le diabète de type 1

Nom du Responsable de l’Unité : Dr. Florence Niedergang

Nom du Responsable de l’Équipe : Pr. R. Mallone/Dr. S. You

Adresse : 123, Bd Port Royal, 75014 Paris