Memory B cells and long-lived plasma cells (LLPCs) are responsible for 30Memory BLow T cell help(mTORC1 lo)Fr.3apoptosisHigh T cell help(mTORC1 hi)GCFr.5Fr.2effective long-term immunity against pathogens. The majority of these cells responding to T cell-dependent antigens are generated from the germinal center (GC) reaction. Indeed, memory B cells emerge from the GC as recir-culating cells and, upon secondary antigen challenge, they are primed to elicit rapid antibody responses.Immunization with NP hapten leads to the accumulation of the high-affinity Abs in a large proportion of LLPCs. Thus, the LLPC pool is thought to be pri-marily composed of specificities possessing the highest affinity for the primary antigen. On the other hand, we and others have recently demonstrated that GC B cells that receive only weak T cell help are preferentially recruited into the memory B cell compartment. Since GC B cells receiving weak T cell help are generally thought to undergo apoptosis, our model has raised the question of how precursors of mature memory B cells are prevented from dying and able to differentiate into memory B cells.To address this question, after identifying a memory-prone population (pro-memory and pre-memory B cells), we have identified key features for these pre-cursor cells to develop into mature memory B cells. We found that pro-memory B cells began to upregulate Bcl2 and cell-surface BCR, contributing to the de-velopment of mature memory B cells. Furthermore, we provide evidence that downregulation of Bcl6 in pro-memory B cells could be one of the regulatory mechanisms to increase Bcl2 and BCR. Together, we propose a model in which weak help from T cells together with provision of an increased survival signal are key for GC B cells to adopt a memory B cell fate. In regard to the increased survival signal, stepwise decreases in Bcl6 expression (pro-memory>pre-memory>mature memory B cells) play a key role.Figure: Fraction 5 GC memory precursor cells acquire increased BCR-mediated survival signalsAfter returning to the light zone (LZ GC B cells), Fraction 3 and 5 LZ GC B cells receive weak T cell help, resulting in low levels of mTORC1, which is one of the prerequisites for development to memory B cells. However, the mTOR-C1low state is necessary but not sufficient. In contrast to Fraction 3 cells, Fraction 5 cells begin to upregulate cell-surface BCR and the anti-apoptotic molecule Bcl2. Hence, both weak T cell help and provision of survival signals by BCR and Bcl2 are required for GC B cells to adopt a memory B cell fate.Recent Major PublicationsInoue T, Shinnakasu R, Kawai C, Ise W, Kawakami E, Sax N, Oki T, Kitamura T, Yamashita K, Fukuyama H, Kurosaki T. Exit from germinal center to become quiescent mem-ory B cells depends on metabolic reprograming and provision of a survival signal. J Exp Med 218, e20200866 (2021)Tanaka S, Ise W, Inoue T, Ito A, Ono C, Shima Y, Sakaki-bara S, Nakayama M, Fujii K, Miura I, Sharif J, Koseki H, Koni PA, Raman I, Li QZ, Kubo M, Fujiki K, Nakato R, Shirahige K, Araki H, Miura F, Ito T, Kawakami E, Baba Y, Kurosaki T. Tet2 and Tet3 in B cells are required to repress CD86 and prevent autoimmunity. Nat Immunol 21, 950-961 (2020)Mesin L, Schiepers A, Ersching J, Barbulescu A, Cavazzoni CB, Angelini A, Okada T, Kurosaki T, Victora GD. Restricted Clonality and Limited Germinal Center Reentry Charac-terize Memory B Cell Reactivation by Boosting. Cell 180, 92-106 (2020)Invited presentationsKurosaki T. “Function of Tet proteins in B cell tolerance” Seminar at Fudan University (Shanghai, China/Online) December 2020Kurosaki T. “B cell and antibody responses against SARS-CoV-2 infections” The 48th Annual Meeting of the Japanese Society of Clinical Immunology (Tokyo, Japan/Online) October 2020Kurosaki T. “Two functional humoral memory compart-ments and their generation mechanism” B Cell Renais-sance: Epigenetics, Regulation and Immunotherapy, Keystone Symposia (Banff, Canada) March 2020Kurosaki T. “Fate Decision germinal center B Cell” Micro-biology Seminar, University of Alabama at Birmingham (Birmingham, USA) February 2020Kurosaki T. “Function of humoral memory compartments and their generation mechanism” New Horizons in B Cell Biology (Shanghai, China) January 2020GCGCDZDZLZLZLaboratory for Lymphocyte DifferentiationTeam Leader: Tomohiro Kurosaki
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