Dendritic cells and immunoregulation in transplantation and immunopathology
Elise Chiffoleau
Team Leader

Research Associate INSERM

Aim. To identify new immunoregulatory cellular and molecular targets in transplantation tolerance and to translate some of these findings to clinical application.

Results. Identification of CLEC-1 and LIMLE as molecules involved in DC function and immuno-modulation and characterization and therapeutic potential of regulatory B cells in transplantation tolerance

Description

Functions of CLEC-1

We previously identified CLEC-1, as being over-expressed in experimental model of allograft tolerance. CLEC-1 belongs to the “C-type lectin receptor” (CLR) family expressed mostly by myeloid cells and that recognize molecular patterns expressed by exogenous and endogenous threats, but also various proteins and lipids (e.g. DECTIN-1). Besides, CLR act as inhibitory or activating receptors to modulate myeloid cell activation, as well as magnitude and quality of downstream T cell response. We previously published that CLEC-1 is expressed in rat by immature myeloid cells and moderates the subsequent Th17 CD4+ T cell response (Thebault et al. 2009). The generation of rat CLEC-1 Fc fusion protein and CLEC-1 knockout rats (in collaboration with the TRIP platform, I Anegon) confirmed its role in DCs in the inhibition of effector Th17 responses (Lopez-Robles MD et al. manuscript in revision). Furthermore, the generation of monoclonal antibodies directed against the extracellular part of human CLEC-1 allow to demonstrate for the first time to our knowledge in Human the cell-surface expression of CLEC-1 on dendritic cells and its role in the inhibition of subsequent Th17 response (Lopez-Robles MD et al. manuscript in revision). Therefore, the patent EP16306381.1 entitled “Patent Methods & pharmaceutical compositions for promoting T cell responses, has been deposit in Oct 2016. Funding: IHU-CESTI (2013-2016), Agence de la Biomédecine (2015-2016)

 

Role of Bregs in tolerance to allografts

In a model of cardiac allograft tolerance in rat induced by short-term immuno-suppression (DSG analog), we previously demonstrated an accumulation in the blood of B cells over-expressing inhibitory molecules (Le Texier et al. 2011) and the presence in the spleen of Bregs able to transfer donor-specific tolerance (Durand et al. 2015). In collaboration with team 4, Bregs with similar phenotype were identified in operationally tolerant patients (Chesneau et al. 2015). This year, we identified a dominant epitope from donor Class II MHC that expand donor-specific Breg cells and that allow their isolation by tetramers (collaboration with SFR Nantes platform “proteins recombinants”). Moreover, we started to determine the Immunoglobumin (Ig) gene repertoire of Breg cells and Ig reactivity profiling at the single cell level in collaboration with the IHU Cesti platform. Indeed, the secretion of Ig by Breg cells and their immunomodulatory properties remain largely uncharacterized. Funding: IHU-CESTI (PIA1) 2011-2016, Prix “Don de soi-Don de vie”. Fondation du rein 2015-2016.