Tuning of in vivo cognate B-T cell interactions by Intersectin 2 is required for effective anti-viral B cell immunity.

Marianne Burbage,Shweta Aggarwal,Michael Way,Usha Nair,Andreas Bruckbauer,Facundo D Batista,Johan Arnold,Francesca Gasparrini,Mauro Gaya

doi:10.7554/elife.26556

Abstract

Wiskott-Aldrich syndrome (WAS) is an immune pathology associated with mutations in WAS protein (WASp) or in WASp interacting protein (WIP). Together with the small GTPase Cdc42 and other effectors, these proteins participate in the remodelling of the actin network downstream of BCR engagement. Here we show that mice lacking the adaptor protein ITSN2, a G-nucleotide exchange factor (GEF) for Cdc42 that also interacts with WASp and WIP, exhibited increased mortality during primary infection, incomplete protection after Flu vaccination, reduced germinal centre formation and impaired antibody responses to vaccination. These defects were found, at least in part, to be intrinsic to the B cell compartment. In vivo, ITSN2 deficient B cells show a reduction in the expression of SLAM, CD84 or ICOSL that correlates with a diminished ability to form long term conjugates with T cells, to proliferate in vivo, and to differentiate into germinal centre cells. In conclusion, our study not only revealed a key role for ITSN2 as an important regulator of adaptive immune-response during vaccination and viral infection but it is also likely to contribute to a better understanding of human immune pathologies.

Highlights

B lymphocytes play an integral part in humoral immunity through their ability to produce high affinity antibodies in response to infections
Itsn2-/- animals consistently presented a 2-fold increase in the number of T follicular helper (Tfh) cells compared to wild type (WT) animals (Figure 3—figure supplement 1A). These results indicate that the reduction observed in germinal centre (GC) formation upon ITSN2 deletion might not result from lack of Tfh cells, instead it is likely to be associated with intrinsic B cell impairment
Through a combination of immunisation and infection experiments in mice lacking ITSN2, we have provided the first analysis of the role of this adaptor protein during immune responses

Summary

Introduction

B lymphocytes play an integral part in humoral immunity through their ability to produce high affinity antibodies in response to infections. One consequence of BCR signalling is antigen internalisation followed by its processing and presentation onto MHC class II, enabling cognate interactions between activated B cells and CD4 T lymphocytes that recognise antigenic peptide-MHC complexes (Lanzavecchia, 1985). These interactions allow B cells to receive T cell help in a contact dependent fashion. The results presented here provide the first characterisation of the role of ITSN2 in the context of immune responses They identify an essential function for this protein in the regulation of B-T cell interactions, germinal centre formation and antibody production, which is reminiscent of the phenotype associated with SAP or CD84 deficiency in T cells

Results

A WT allele

Discussion

Materials and methods

Funding Funder Cancer Research UK