Leader

• 

  Saveanu Loredana

  • 01 57 27 74 90
  • loredana.saveanu@inserm.fr

• Guermonprez Pierre

  • 01 57 27 74 90
  • pierre.guermonprez@inserm.fr

Presentation

Antigen Presentation by Dendritic Cells to T cells

Dendritic cells (DCs) are the sentinel cells of the immune system. DCs present antigen to T lymphocytes and regulate their activation. T lymphocytes recognize and eliminate infected or cancer cells. Therefore, understanding the biology of T cell activation by DCs is crucial for the development of vaccines and immunotherapies. Also, inappropriate regulation of T lymphocyte activation by DCs supports the development of chronic inflammatory diseases and auto-immunity.

Our team investigates the mechanisms underpinning T cell activation by DCs. We implement multi-scale and multi-disciplinary approaches to tackle 3 research topics.

1- Ontogeny and dynamics of DC populations.

At homeostasis, DCs populations are continuously renewed from bone marrow hematopoietic stem cells. The dynamics of DCs population impacts on immune responses. We aim at understanding: i) the ontogenetic processes enabling the production of various DCs subsets (classical and inflammatory) and its regulation during cancer; ii) how DCs traffic to solid tumours. This project implements contemporary technologies such as high dimensional profiling, single cell RNAseq as well as humanised mice models. Building on a better understanding of DC populations, we design and evaluate therapeutic interventions aiming at increasing DC infiltration in solid tumours to stimulate anti-tumour immunity.

2- Antigen cross-presentation/presentation by MHCI/II.

In most instances, induction of antigen-specific T cell responses relies on the phagocytosis of particulate antigens by DCs. This is highly relevant for tumour antigens that are engulfed together with cancer cell debris. The dynamics of antigen-containing phagosomes is controlled by their interactions with multiple types of endosomes (early, storage, late, lysosomes). These interactions ultimately control the formation and presentation of antigenic peptides-MHC I and II complexes. We investigate if and how phagosome-associated proteins control phagosome dynamics and antigen presentation by MHCI/II to T lymphocytes in DCs subsets. Both, unbiased genetic screen using CRISPR-Cas9 and hypothesis driven approaches (Rab GTPases and PI3Kinases) are developed in the lab to tackle the molecular cell biology of antigen presentation by DCs.

3- T lymphocyte activation, fate and function.

The recognition of MHC-peptide complex by the T cell receptor leads to the formation of the immune synapse. We aim at understanding how intracellular trafficking in T lymphocytes supports the recognition of MHC-peptides complexes by the T cell receptor. Using intracellular live imaging, advanced microscopy techniques (FRET) and cutting-edge proteomics (in vivo biotynilation via APEX2), we investigate the endocytic mechanisms controlling TCR signalling at the DC-T cell synapse. Specifically, we are addressing how the balance between recycling or degradation of several key proteins for T cell activation such as TCRzeta, Lck and LAT controls signalling downstream TCR triggering.

In addition, we investigate the long-term consequences of antigen presentation by DCs subsets on the differentiation, fate and function of T lymphocytes. DCs are composed of multiple subsets which are also regulated by context-dependent signals. We are investigating how cell-intrinsic DCs features and environmental cues (including factors from the tumour micro-environment) shape the diversity of antigen-presenting DCs and anti-tumour T cell responses. In particular, we investigate how DCs imprint some trafficking behaviour in T cells and impact on T cell fate in the context of breast and lung cancer.