RESUMEN
Diverse and rapidly mutating viruses pose challenges to immunogen and vaccine design. In this study, we evaluated the ability of memory B-cells obtained from two independent NHP trials to cross-react with individual HIV-1 vaccine components of two different multivalent immunization strategies. We demonstrated that while an HIV-1 Env multiclade, multivalent immunization regimen resulted in a dominant memory B-cell response that converged toward shared epitopes, in a sequential immunization with clonally-related non-stabilized gp140 HIV-1 Envs followed by SOSIP-stabilized gp140 trimers, the change in immunogen format resulted in repriming of the B-cell response.
RESUMEN
Regulation of BCR signaling has important consequences for generating effective Ab responses to pathogens and preventing production of autoreactive B cells during development. Currently defined functions of Fc receptor-like (FCRL) 1 include positive regulation of BCR-induced calcium flux, proliferation, and Ab production; however, the mechanistic basis of FCRL1 signaling and its contributions to B cell development remain undefined. Molecular characterization of FCRL1 signaling shows phosphotyrosine-dependent associations with GRB2, GRAP, SHIP-1, and SOS1, all of which can profoundly influence MAPK signaling. In contrast with previous characterizations of FCRL1 as a strictly activating receptor, we discover a role for FCRL1 in suppressing ERK activation under homeostatic and BCR-stimulated conditions in a GRB2-dependent manner. Our analysis of B cells in Fcrl1 -/- mice shows that ERK suppression by FCRL1 is associated with a restriction in the number of cells surviving splenic maturation in vivo. The capacity of FCRL1 to modulate ERK activation presents a potential for FCRL1 to be a regulator of peripheral B cell tolerance, homeostasis, and activation.
