Abstract

Humoral immunity to common viral and vaccine antigens can provide lifelong protection against infection and this protection is partially mediated through memory B cells. Combined immunodeficiency patients with a novel mutation in the kinase STK4 were found to have decreased number of memory B cells. To study the underlying immune defects in these patients, a mouse model with the same mutation in Stk4 was generated by CRISPR /Cas9 gene editing. Using this mouse model, this mutation was shown to be pathogenic and result in an intrinsic defect in B cell development, the germinal centre response, secretion of antigen-specific antibodies, and the formation of memory B cells. This reveals a previously unknown role for STK4 in the humoral immune response. We have also studied the re-activation and differentiation of MBCs. Utilising two-photon microscopy, we found MBCs were preferentially located in the subcapsular region of the draining lymph node where they continuously scan CD169 + subcapsular sinus macrophages for antigen in the steady state. Unexpectedly, we found that upon antigen recall, memory B cells are rapidly reactivated to proliferate and differentiate into short-lived antibody-secreting plasmablasts in this subcapsular region, in a previously unappreciated structure we have named the subcapsular proliferative foci (SPF). This SPF is a dynamic transient microanatomical compartment that is structurally and functionally distinct from the germinal centre. Thus, focused delivery of antigen and T cell help to memory B cells within the SPF may explain the rapid kinetics of the secondary antibody response.