Schematic overview of the activation and differentiation pathways of human B cells targeting PfCSP. (A) Naive CD4⁺ Th cells are primed by dendritic cells (DCs), which process and present PfCSP antigens on MHC-II molecules in the T cell zone of secondary lymphoid organs (SLOs). (B) Naive CD4 Th cells differentiate into Th1 effector cells and exit the SLO or differentiate into precursor T_fh cells (pre-T_fh) and migrate to the border of the T cell zone and the B cell follicle, where they interact with B cells that have been activated by antigen. (C and D) Antigen-activated B cells and pre-T_fh cells differentiate into memory B cells and short-lived plasma cells or cT_fh cells, respectively, and exit the SLOs or migrate into the B cell follicle to form GCs. In GCs, B cells undergo affinity maturation upon the induction of somatic hypermutations followed by competition for antigen presented on follicular dendritic cells (FDCs) and survival signals from T_fh cells after antigen uptake and presentation on MHC-II molecules. (E and F) PfCSP-reactive B cells can undergo either classical affinity maturation (E) by acquisition of mutations that enhance interactions with the antigen or by homotypic affinity maturation (F) through the selection of mutations that facilitate the interaction with B cell receptors bound to neighboring epitopes on the same antigen, e.g., B cell receptors with Ig chains encoded by IGHV3-33 and IGKV1-5 gene segments that recognize NANP motifs in PfCSP (Imkeller et al., 2018; Oyen et al., 2018). (G) Upon positive selection, affinity-matured B cells differentiate into memory B cells or plasma cells, some of which exit the SLO, home to the bone marrow, and become long lived. A fraction of GC T_fh cells exits the SLO, enters the circulation, and predominantly adopts a Th1-like phenotype characteristic for Pf infection (Obeng-Adjei et al., 2015; Chan et al., 2020).