@article {Zhue201900506, author = {Zilu Zhu and Ashima Shukla and Parham Ramezani-Rad and John R Apgar and Robert C Rickert}, title = {The AKT isoforms 1 and 2 drive B cell fate decisions during the germinal center response}, volume = {2}, number = {6}, elocation-id = {e201900506}, year = {2019}, doi = {10.26508/lsa.201900506}, publisher = {Life Science Alliance}, abstract = {The PI3K pathway is integral for the germinal center (GC) response. However, the contribution of protein kinase B (AKT) as a PI3K effector in GC B cells remains unknown. Here, we show that mice lacking the AKT1 and AKT2 isoforms in B cells failed to form GCs, which undermined affinity maturation and antibody production in response to immunization. Upon B-cell receptor stimulation, AKT1/2{\textendash}deficient B cells showed poor survival, reduced proliferation, and impaired mitochondrial and metabolic fitness, which collectively halted GC development. By comparison, Foxo1T24A mutant, which cannot be inactivated by AKT1/2 phosphorylation and is sequestered in the nucleus, significantly enhanced antibody class switch recombination via induction of activation-induced cytidine deaminase (AID) expression. By contrast, repression of FOXO1 activity by AKT1/2 promoted IRF4-driven plasma cell differentiation. Last, we show that T-cell help via CD40, but not enforced expression of Bcl2, rescued the defective GC response in AKT1/2{\textendash}deficient animals by restoring proliferative expansion and energy production. Overall, our study provides mechanistic insights into the key role of AKT and downstream pathways on B cell fate decisions during the GC response.}, URL = {https://www.life-science-alliance.org/content/2/6/e201900506}, eprint = {https://www.life-science-alliance.org/content/2/6/e201900506.full.pdf}, journal = {Life Science Alliance} }