ePoster Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

Stochastic clonal regulation of antibody class switching (#196)

Miles Horton 1 2 , HoChan Cheon 3 , Ken R Duffy 3 , Daniel Brown 1 2 , Carolina Alvarado 1 2 , Joanna R Groom 1 2 , Shalin H Naik 1 2 , Susanne Heinzel 1 2 , Philip D Hodgkin 1 2
  1. Walter and Eliza Hall Institute, North Melbourne, VIC, Australia
  2. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia
  3. Hamilton Institute, Maynooth University, Maynooth, Ireland

The ability of B lymphocytes to secrete antibody of different isotypes is essential for effective humoral immunity, however the clonal origins and quantitative principles driving the emergence of B cell heterogeneity are complex and poorly defined. Here we identify multiple intersecting orthogonal mechanisms that govern alternate clonal fate allocation by activated B cells. One is deterministic and exerts strong clonal imprinting on antibody secreting cell (ASC) differentiation fate. A second is highly stochastic, in which clonal ancestry exerts little control over class switch recombination (CSR) and isotype selection. Clonal regulation of CSR is in turn driven by two independent and stochastic molecular events, the expression of activation-induced cytidine deaminase (AID) and germline transcription. A mathematical model accounting for the intersection of these latter two independent processes predicted isotype switching fates in vitro and in vivo . That multiple activated B cell fates emerge according to identifiable, lineage-dependent, quantitative rules provides insight into how the immune system has evolved to ensure the automatic generation of diverse antibody types through cellular programming.