Project 1 : IL-2/BACH2 axis in B cell fate decisions during humoral immune response in health and disease

Juliette Gauthier (PhD student), Simon Leonard (engineer), Alexis Grasseau (postdoctoral fellow) , Olivier Decaux (PU-PH), Céline Delaloy (CRCN INSERM)

State-of-the-art and Previous results

T cell help to B cell is the limited factor to access the germinal center (GC) and produce plasma cells  (PCs) secreting high affinity antibodies. Two cognate bidirectional interactions between B cell and helper T cells are required at the T/B border and in the GC. Common gc cytokines, IL-2 IL-4 IL-21, are key elements of T cell help. In contrast to IL-4 and IL-21, the full extent of IL-2 as either a key early and/or late determinant of terminal B cell differentiation is currently limited.

At the molecular level transition of B cells into plasma cells is governed by a tightly interconnected network of TFs, the chronology and hierarchy is not well understood. The BTB and CNC homology 2 (BACH2) is a transcriptional repressor controlling multiple differentiation fates in activated B cells to yield GC cells, memory cells and PCs for effective humoral immunity (Figure 1). Several studies suggest that BACH2 is involved in the development of lymphomas and autoimmunity. However BACH2 temporal regulation and function in the process of B cell activation remains to be studied.

Figure 1 Model of effects of IL-2 and BACH2 on B cell fate decisions near the germinal center

We described recently the fine molecular events that happened when activated human naive B cells are primed to differentiate into PCs in vitro by an early IL-2-dependent mechanism (Hipp et al. Nat Comm 2017). We identify the transcriptional repressor BACH2 as a major effector of the IL-2/ERK/ELK1 signalling pathway (Figure 2).

                                                                                      Figure 2 Effect of IL-2 on human B cell fate in vitro

Using an in vitro model of plasma cell differentiation we demonstrated that IL-2 imprints differentiation fate in human activated B cells to yield plasma cells. The times repression of BACH2 through IL-2 mediated ERK/ELK1 pathway directs plasma cell lineage commitment (Hipp et al. Nat Comm 2017).

• Study the effect of IL-2 on B cell fate in vivo: timing and molecular mechanisms,
• Investigate the specific contribution of IL-2 on B cell in inflammatory context in collaboration with Laure Michel and Patricia Amé (Team 2),
• Study the temporal resolution of transcriptional dynamics regulating plasma cell differentiation at the level of single cell fate decision,
• Investigate how temporal alteration of BACH2 expression gives rise to abnormal immune responses in lymphoproliferative disorders