Heterogeneity of B cell immune responses

Prof Victor Tybulewicz; The Francis Crick Institute

Victor Tybulewicz obtained his PhD at the MRC Laboratory of Molecular Biology in Cambridge working on the ATP synthase. His postdoctoral research at the Whitehead Institute, MIT, Cambridge MA, USA, was focussed around developing methods to target genes in embryonic stem cells, and he was one of the first people to make a 'knock-out' mouse. He moved to the UK to set up his research group at the MRC National Institute for Medical Research, which subsequently merged into the Francis Crick Institute. Victor Tybulewicz is currently a Principal Group Leader and Associate Research Director at the Francis Crick Institute. He has two main research interests. Firstly, he studies signal transduction pathways in lymphocytes that regulate development, activation, survival, migration and adhesion. Using mouse genetics, biochemistry and cell biology approaches he has defined multiple roles for the SYK kinase, the VAV1 exchange factor and for its substrates RAC1 and RAC2 in B and T cell physiology. Currently, he is studying a pathway controlled by the WNK1kinase which plays a critical role in B and T cell activation, migration and adhesion. In addition, his group is interested in how BAFFR transduces signals that control B cell survival, and in the differentiation and function of memory B cells. In a second research interest, in collaboration with Elizabeth Fisher (UCL) he has generated a series of mouse models of Down Syndrome (trisomy 21) and is using these to identify the genes that are required in three copies to cause specific Down Syndrome phenotypes, including congenital heart defects, craniofacial deficits and cognitive impairment.

The mature B cell compartment consists of follicular (FO) and marginal zone (MZ) B cells, and B1 cells. These differ in their repertoire of B cell antigen receptors (BCRs) - broad for FO and MZ B cells, narrow for B1 cells - in their antigenic specificity and in their anatomical locations. Following activation by antigen, B cells proliferate and differentiate into germinal centre cells, antibody-secreting plasma cells and memory B cells (MBCs). In my seminar I will present work on two aspects of B cell biology. The development of MBCs is poorly understood. Using a Cre-based fate reporter and single cell RNAseq we have revealed an unexpected heterogeneity of MBC populations, varying in isotype, mutational burden and surface phenotype. These MBC subsets correspond to different types of naive Bcells: FO, MZ and B1 B cells. Furthermore, amongst FO-like MBC there are cells that are transcriptionally almost indistinguishable from naive FO B cells (FO-I MBC) and others that are more distinct (FO-II MBC). Transcription factor expression and activity varied between MBC subsets. Specifically, we find that KLF2 is upregulated in FO-II MBC and is required for their generation from germinal centre Bcells. TACI, a member of the TNF receptor superfamily, is expressed on all mature B cells, with highest levels on MZ B cells and plasma cells. Previous studies reported that TACI is a negative regulator of B cell survival. However, this conclusion is confounded by elevated levels of BAFF, a cytokine that supports B cell survival, in TACI-deficient mice. We now show that TACI does not directly regulate B cell survival in mice but rather has a cell-intrinsic role in MZ B cell development. Mechanistically, TACI is required for MZ B cell development from T2 B cell precursors via activation of the PI3K-AKT pathway and subsequent inhibition of the FOXO1 transcription factor. Our work has implications for human immunodeficiency and autoimmunity.