Maintaining diversity while maximising affinity - IL-21 and the balancing act of B cell selection

Dr Isaak Quast; Monash University 

I am an immunologist with an additional focus on protein biochemistry and virology. I studied biology in Vienna, Austria and pursued a PhD at the University of Zürich, Switzerland. My PhD work provided insights into how small structural changes in antibody-linked glycans modulate effector functions and the implications this has for antibody-mediated autoimmunity. For my postdoctoral research I joined the laboratory of Prof. David Tarlinton to study the cellular and molecular mechanisms regulating the generation and diversification of antibodies. I currently hold a position as a senior research fellow and group leader at Monash University, Melbourne, Australia where my research is focused on providing the fundamental knowledge required for guiding the magnitude and specificity of the immune response to vaccination.

Germinal center (GC) formation in response to infection or vaccination relies on the coordinated behavior of T and B cells. IL-21, a pleiotropic, T cell derived cytokine, is a central modulator of GC size, maintenance and output and studying how it exerts its actions provides an opportunity to understand GC dynamics. Following this theorem, we genetically restricted IL-21 production and receipt in vivo to show how its independent actions on T and B cells combine to regulate the GC. During response initiation, IL-21 promotes CD4 T cell expansion and Tfh differentiation in a dose-dependent, paracrine manner. Simultaneously, by activating AKT and S6, IL-21 accelerates cell cycle progression and the rate of cycle entry of B cells, increasing their contribution to the ensuing GC. Within GC, IL-21 specifically promotes B cell centroblast identity and, when bioavailability is high, plasma cell differentiation. Critically, these actions occur irrespective of cognate T:B interactions, making IL-21 a general promoter of growth rather than exclusively mediating affinity-driven selection. I will discuss these findings and their implications for understanding how GCs balance maintaining a diverse repertoire of reactivities with selecting cells for high affinity antibody output, thereby achieving optimal protective immunity.