Cognate control of antigen specific memory B cell development

• Applicant: Dr. Eduard Urich
• Subject Area: Immunology
• Term: from 2008 to 2009
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 69342665

The germinal centre (GC) is an important site within lymphoid tissues where B cell response to antigen (Ag) is amplified and refined in specificity. This proposal focuses on the mode of B-T cell interaction in GCs and how this interaction controls the development of memory B cells. Ag-specific GC B cells compete for Ag on follicular dendritic cells to receive survival signals, but we assume that this alone does not account for the complex selection of B cells. We propose a two step selection model in which higher-affinity B cells present more Ag in the context of MHCII and therefore have a greater capacity to receive help from a specialized subset of follicular T helper (TFH) cells. Using the hen egg lysozyme (HEL) model, we will test the hypothesis that GC B cells expressing the highest affinity BCR also express the highest levels of peptide MHCII (pMHCII) on their surface. We have direct experimental access to HEL-specific GC B cell in vivo and we are also able to measure pMHCII surface levels and B cell receptor affinity. Furthermore, we will characterize Ag-specific GC TFH cells. This will be performed by adoptive transfer of HEL-specific transgenic T cells and by monitoring the phenotype of these cells at the peak of the GC reaction. Finally, we will investigate the influence of Ag-specific GC TFH cells on the clonal evolution of high-affinity memory B cells. This will be addressed using inhibitory antibodies against TCR-pMHCII interaction, co-stimulatory and adhesion molecules in vivo and ex vivo in a 3 dimensional lymphoid tissue equivalent.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Dr. Michael McHeyzer-Williams