Memory B cell commitment, maintenance and terminal differentiation

2006 Fiscal Year Final Research Report Summary

• Project/Area Number: 16043261
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: RIKEN (2006); National Institute of Infectious Diseases (2004-2005)
• Principal Investigator: TAKEMORI Toshitada RIKEN, Lab. For Immunological Memory, Group Director, 免疫記憶研究グループ, グループディレクター (60114295)
• Co-Investigator(Kenkyū-buntansha): KAJI Tomohiro RIKEN, Lab. For Immunological Memory, Researcher, 免疫記憶研究グループ, 研究員 (70370963) ; OHARA Osamu RIKEN, Lab. For Immunogenomics, Group Director, 免疫ゲノミク研究グループ, グループディレクター (20370926) ; HIKITA Masaki RIKEN, Iab. For Lymphocyte Differentiation, Researcher, 分化制御研究グループ, 研究員 (60228715) ; TAKAHASHI Yoshimasa National Institute of Infectious Diseases, Dept. Immunology, Researcher, 免疫部, 主任研究員 (60311403)
• Project Period (FY): 2004 – 2006
• Keywords: memory B cell / memory B cell genes / survival / secondary response / SMN / AIF / committment / AID / Somatic mutations

Research Abstract

Memory B cells acquire several intrinsic properties that differ from na・e B cells, suggesting that memory B cells may have a unique gene expression that differs quantitatively and/or qualitatively from other stages of B cells. Therefore, to clarify the mechanism responsible for memory B cell commitment, survival and terminal differentiation upon antigen reexposure, we identified changes in gene expression that occur in the transition from a naive B cell to either GC B cells, memory B cells or plasma cells upon antigen stimulation. We have cloned several genes which are highly expressed in memory B cells, including E52 and 4010. E52 was turned out to be a human homologue of the survival of motor neuron gene (SMN)1, which is a causative gene for spinal muscular atrophy (SMA). Over expression of SMN in B cell lymphoma cell lines prolonged cell survival in proapoptotic culture conditions, raising the idea that the gene could be responsible for memory B cell survival. Therefore, we characte rized the role of SMN in cell survival by biochemical analysis and concluded that SMN prolonged cell survival upon oxidant stress and enhanced the activity of the mitochondrial respiratory chain complex I.
The 4010 gene encodes an adopter molecule and its overexpression in splenic B cells results in an augmentation of IgG1 response upon stimulation with anti-Igs and anti-CD40 mAbs in vitro. Thus, 4010 could be involved in the signaling cascade responsible for either memory B cell terminal differentiation or antibody secretion. To examine this possibility we are now establishing conditional knock out mice.
To know the regulatory network responsible for memory B cell commitment, we utilized Affymetrix GeneChip analysis and characterize the changes in gene expression in the transition from naive B cells to GC B cells, memory B cells or plasma cells upon antigen stimulation. Q-PCR confirmation revealed that memory B cell population expressed a group of transcripts selectively enriched in this population, with similar time-dependent changes in their expression patterns. To utilize such genetic markers for the memory B cell lineage, we analyzed the early events in antigen-specific B cell response and suggested that activated B cells progress to memory B cells, at least, from day 5 to day 6 after immunization, accompanied by class-switch recombination and efficient proliferation.

Research Products

• [Journal Article] The agnathan lamprey diversifies antigen receptor genes by shifting junctions during gene rearrangemen (2007)
  • Author(s): Nagawa, F., Kishishita, N., Shimizu, K., Hirose, S., Miyoshi, M., Nezu, J., Nishimura, T., Nishizumi, H., Takeuchi, M., Miyajima, A., Hashimoto, S., Takahashi, Y., Toshitada Takemori, T.Otsuka, A.-J., Sakano, H.
  • Journal Title: Nature Immunol. 8 Pages: 206-13
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The agnathan lamprey diversifies antigenreceptor genes by shifting junctions during gene rearrangement. (2006)
  • Author(s): Nagawa, F, Kishishita, N, Shimizu, K, Hirose, S, Miyoshi, M, Nezu, J, Nishimura, T, Nishizumi, H, Takeuchi, M, Miyajima, A, Hashimoto, S, Takahashi, Y, Toshitada Takemori, T, Otsuka, A.-J, Sakano, H.
  • Journal Title: Nature Immunol. 8 Pages: 206-13
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] B7-H1-induced apoptosis as a mechanism of immune privilege of corneal allografts. (2006)
  • Author(s): Hori, J., Wang, M., Miyashita, M., Tanemoto, K., Takahashi, H., Takemori, T., Okumura, K., Yagita, H., Azuma, M.
  • Journal Title: J. Immunol. 177 Pages: 5928-5935
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Two waves of memory B cellgeneration in the primary immune response. (2005)
  • Author(s): Inamine, A, Takahashi, Y, Tokuhisa, T, Miyae K, Takemori, T, Abe, R.
  • Journal Title: Int. Immunol. 17 Pages: 581-589
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] A unique role of Ras in memoryB cell response. (2005)
  • Author(s): Takahashi, Y, Inamine A, Hashimoto, S.-I, Yoshioka, E, Kojima, N, Abe, R, Takemroi T.
  • Journal Title: Immunity 23 Pages: 127-138
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Interferon regulatory factor-4 negatively regulates the product of proinfalmmatory cytokines by macrophages in response to LPS. (2005)
  • Author(s): Honnma, K, Udono, H, Ohkusu-Tsukada, K, Khono, T, Yamamoto, K, Ogawa, A, Takemori, T, Kumatori, A, Suzuki, S, Matsuyama, T, Yui, K.
  • Journal Title: Proc. Natl. Acad. Sci. USA 102 Pages: 16001-16006
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] B7-H1-induced apoptosis as a mechanism of immune privilege of corneal allografts. (2005)
  • Author(s): Hori, J, Wang, M, Miyashita, M, Tanemoto, K, Takahashi, H, Takemori, T, Okumura, K, Yagita, H, Azuma, M.
  • Journal Title: J. Immunol. 177 Pages: 5928-5935
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Two waves of memory B cell generation in the primary immune response. (2005)
  • Author(s): Inamine, A., Takahashi, Y., Tokuhisa, T., Miyae K., Takemori, T., Abe, R.
  • Journal Title: Int. Immunol. 17 Pages: 581-589
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A unique role of Ras in memory B cell response. (2005)
  • Author(s): Takahashi, Y., Inamine A., Hashimoto, S.-I., Yoshioka, E., Kojima, N., Abe, R., Takemroi T
  • Journal Title: Immunity 23 Pages: 127-138
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Interferon regulatory factor-4 negatively regulates the product of proinfalmmatory cytokines by macrophages in response to LPS. (2005)
  • Author(s): Honnma, K., Udono, H., Ohkusu-Tsukada, K., Khono, T., Yamamoto, K., Ogawa, A., Takemori, T.Kumatori, A., Suzuki, S., Matsuyama, T., Yui, K.
  • Journal Title: Proc. Natl. Acad. Sci. USA 102 Pages: 16001-16006
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] An essentialrole for the RNA-pr b GANP for somatic hypermu tation of immunoglobulin gene in germinal center B cells. (2004)
  • Author(s): Kuwahara, K, Fujita, S, Takahashi, Y, Xing, Y, Nakagata, N, Takemori, T, Aizawa, S, Sakaguchi, N.
  • Journal Title: Pric, Natl. Acad. Sci. USA 101 Pages: 1010-1015
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] An essential role for the RNA-pr b GANP for somatic hypermutation of immunoglobulin gene in germinal center B cells. (2004)
  • Author(s): Kuwahara, K., Fujita, S., Takahashi, Y., Xing, Y Nakagata, N., Takemori, T., Aizawa, S.Sakaguchi, N.
  • Journal Title: Proc. Natl. Acad. Sci. USA 101 Pages: 1010-1015
  • Description: 「研究成果報告書概要(欧文)」より