Innate like and CD4+ T Cells in Cancer

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Olivier Lantz Team Leader Tel:

Our group studies in vivo T cell biology in mouse and human models.

We are focusing on three main topics:

1) Study of the mucosal associated invariant T (MAIT) cells: an evolutionarily conserved T cell selected by MHC-related protein I (MR1) on gut B cells. MAIT cells are the most abundant innate like T cells in humans where they represent 1-8 and 20-40 % of blood and liver T cells, respectively.

We have discovered a T cell sub population whose specificity is conserved between species characterized by the use of an invariant chain, the Vα7.2/19-Jα33 TCRα chain. These cells are localized in the gut lamina propria and require the presence of B cells in the same location both in humans and in mice. These T cells are called Mucosal associate invariant T cells (MAIT) and are selected by the MHC related molecule 1, MR1 which is also highly conserved between species.

We showed that MAIT cells development is a stepwise process with an intra-thymic MR1 dependent but B cell and commensal flora independent selection process followed by a peripheral maturation and expansion requiring B cells and the commensal flora.

MAIT cells are activated and secrete Interferon-g after stimulation by fibroblasts or antigne presenting cells co-cultured with bacteria and yeasts but not viruses. MAIT cells migrate to the site of bacterial infection both in humans and mice. They display protective function in 2 models of infectious disease. Expression of the multidrug-receptor transporter would explain the ability of MAIT cells to resist the xenobiotics secreted by bacteria while the capacity to secrete IL-17 would fit with their anti-bacterial activity.

We have developed a new mouse model harboring a high number of MAIT cells that are also fluorescent by introgressing both a wild mouse gene and a ror(gt) GFP transgene. This will allow us to study how MAIT cells are protective against specific infections.

2) Study of the interactions between tumors expressing nominal antigens in a constitutive or inducible way and specific T cells

Growth of "spontaneous" lung tumors expressing a nominal antigen leading to the proliferation of specific T cells in the draining mediastinal lymph-node Mice harboring an inducible constitutively active K-Ras received a virus coding for a luciferase, the antigen and a Cre recombinase intra-tracheally. Tumors appear as light emitting mass in the lund. Specific Marilyn CD4 T cells recognizing the tumor antigen were injected at week 23 and analysis was carried out 3 weeks later.
Growth of “spontaneous” lung tumors expressing a nominal antigen leading to the proliferation of specific T cells in the draining mediastinal lymph-node
Mice harboring an inducible constitutively active K-Ras received a virus coding for a luciferase, the antigen and a Cre recombinase intra-tracheally. Tumors appear as light emitting mass in the lund. Specific Marilyn CD4 T cells recognizing the tumor antigen were injected at week 23 and analysis was carried out 3 weeks later.

Our goal is to better understand the relationship between tumors expressing a nominal antigen at a given time and location, and a minimal immune system specific for that same antigen. Using transplantable tumor models expressing antigen in an inducible manner or spontaneous tumor models expressing nominal antigens, we try to decipher whether the tumor is ignored or leads to deletion, anergy or class switch of the specific immune response or generate suppressor T cells.

The models have been implemented (Figure) and the immune response is being analyzed. These same models are used to develop new anti-cancer vaccines based on long peptide or DNA vaccination targeting the antigen to antigen presenting cells. Treatments associating vaccinations and chemotherapy are also tested.

3) Study of the immune response during the treatment of cancer patients.

We show that the CD4 T cells are aware of the tumor since the early stages since an increased number of CD4 T cells displaying signs of chronic activation are found in the blood of patients harboring small tumors. We are now analysing the specificity of these cells.

 

Key publications

Year of publication 2019

François Legoux, Déborah Bellet, Celine Daviaud, Yara El Morr, Aurelie Darbois, Kristina Niort, Emanuele Procopio, Marion Salou, Jules Gilet, Bernhard Ryffel, Aurélie Balvay, Anne Foussier, Manal Sarkis, Ahmed El Marjou, Frederic Schmidt, Sylvie Rabot, Olivier Lantz (2019 Aug 31)

Microbial metabolites control the thymic development of mucosal-associated invariant T cells.

Science (New York, N.Y.) : DOI : eaaw2719
François Legoux, Jules Gilet, Emanuele Procopio, Klara Echasserieau, Karine Bernardeau, Olivier Lantz (2019 Aug 22)

Molecular mechanisms of lineage decisions in metabolite-specific T cells.

Nature immunology : 1244-1255 : DOI : 10.1038/s41590-019-0465-3
Olivier Lantz, François Legoux (2019 May 30)

MAIT cells: programmed in the thymus to mediate immunity within tissues.

Current opinion in immunology : 75-82 : DOI : S0952-7915(18)30079-7

Year of publication 2018

Marion Salou, François Legoux, Jules Gilet, Aurélie Darbois, Anastasia du Halgouet, Ruby Alonso, Wilfrid Richer, Anne-Gaëlle Goubet, Céline Daviaud, Laurie Menger, Emanuele Procopio, Virginie Premel, Olivier Lantz (2018 Dec 7)

A common transcriptomic program acquired in the thymus defines tissue residency of MAIT and NKT subsets.

The Journal of experimental medicine : 133-151 : DOI : 10.1084/jem.20181483
Ruby Alonso, Héloïse Flament, Sébastien Lemoine, Christine Sedlik, Emanuel Bottasso, Isabel Péguillet, Virginie Prémel, Jordan Denizeau, Marion Salou, Aurélie Darbois, Nicolás Gonzalo Núñez, Benoit Salomon, David Gross, Eliane Piaggio, Olivier Lantz (2018 May 31)

Induction of anergic or regulatory tumor-specific CD4 T cells in the tumor-draining lymph node.

Nature communications : 2113 : DOI : 10.1038/s41467-018-04524-x

Year of publication 2016

Katarzyna Franciszkiewicz, Marion Salou, Francois Legoux, Qian Zhou, Yue Cui, Stéphanie Bessoles, Olivier Lantz (2016 Jun 21)

MHC class I-related molecule, MR1, and mucosal-associated invariant T cells.

Immunological reviews : 120-38 : DOI : 10.1111/imr.12423
All publications