Kaji, TomohiroIshige, AkikoHikida, MasakiTaka, JunkoHijikata, AtsushiKubo, MasatoNagashima, TakeshiTakahashi, YoshimasaKurosaki, TomohiroOkada, MarikoOhara, OsamuRajewsky, KlausTakemori, Toshitada2013-10-182012Kaji, Tomohiro, Akiko Ishige, Masaki Hikida, Junko Taka, Atsushi Hijikata, Masato Kubo, Takeshi Nagashima, et al. 2012. Distinct cellular pathways select germline-encoded and somatically mutated antibodies into immunological memory. The Journal of Experimental Medicine 209(11): 2079-2097.0022-1007http://nrs.harvard.edu/urn-3:HUL.InstRepos:11185779One component of memory in the antibody system is long-lived memory B cells selected for the expression of somatically mutated, high-affinity antibodies in the T cell–dependent germinal center (GC) reaction. A puzzling observation has been that the memory B cell compartment also contains cells expressing unmutated, low-affinity antibodies. Using conditional Bcl6 ablation, we demonstrate that these cells are generated through proliferative expansion early after immunization in a T cell–dependent but GC-independent manner. They soon become resting and long-lived and display a novel distinct gene expression signature which distinguishes memory B cells from other classes of B cells. GC-independent memory B cells are later joined by somatically mutated GC descendants at roughly equal proportions and these two types of memory cells efficiently generate adoptive secondary antibody responses. Deletion of T follicular helper (Tfh) cells significantly reduces the generation of mutated, but not unmutated, memory cells early on in the response. Thus, B cell memory is generated along two fundamentally distinct cellular differentiation pathways. One pathway is dedicated to the generation of high-affinity somatic antibody mutants, whereas the other preserves germ line antibody specificities and may prepare the organism for rapid responses to antigenic variants of the invading pathogen.en-USJournal Article2013-10-1810.1084/jem.20120127