Exit from germinal center to become quiescent memory B cells depends on metabolic reprograming and provision of a survival signal
A still unanswered question is what drives the small fraction of activated germinal center (GC) B cells to become long-lived quiescent memory B cells. We found here that a small population of GC-derived CD38intBcl6hi/intEfnb1+ cells with lower mTORC1 activity favored the memory B cell fate. Constitu...
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| Published in | The Journal of experimental medicine Vol. 218; no. 1 |
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| Main Authors | , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
Rockefeller University Press
04.01.2021
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| Online Access | Get full text |
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| Abstract | A still unanswered question is what drives the small fraction of activated germinal center (GC) B cells to become long-lived quiescent memory B cells. We found here that a small population of GC-derived CD38intBcl6hi/intEfnb1+ cells with lower mTORC1 activity favored the memory B cell fate. Constitutively high mTORC1 activity led to defects in formation of the CD38intBcl6hi/intEfnb1+ cells; conversely, decreasing mTORC1 activity resulted in relative enrichment of this memory-prone population over the recycling-prone one. Furthermore, the CD38intBcl6hi/intEfnb1+ cells had higher levels of Bcl2 and surface BCR that, in turn, contributed to their survival and development. We also found that downregulation of Bcl6 resulted in increased expression of both Bcl2 and BCR. Given the positive correlation between the strength of T cell help and mTORC1 activity, our data suggest 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. |
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| AbstractList | Inoue et al. show that a small population of germinal center–derived CD38
int
Bcl6
hi/int
Efnb1
+
cells with lower mTORC1 activity favors a memory B cell fate. This population also has higher levels of Bcl2 and surface BCR that, in turn, contributes to their survival and development.
A still unanswered question is what drives the small fraction of activated germinal center (GC) B cells to become long-lived quiescent memory B cells. We found here that a small population of GC-derived CD38
int
Bcl6
hi/int
Efnb1
+
cells with lower mTORC1 activity favored the memory B cell fate. Constitutively high mTORC1 activity led to defects in formation of the CD38
int
Bcl6
hi/int
Efnb1
+
cells; conversely, decreasing mTORC1 activity resulted in relative enrichment of this memory-prone population over the recycling-prone one. Furthermore, the CD38
int
Bcl6
hi/int
Efnb1
+
cells had higher levels of Bcl2 and surface BCR that, in turn, contributed to their survival and development. We also found that downregulation of Bcl6 resulted in increased expression of both Bcl2 and BCR. Given the positive correlation between the strength of T cell help and mTORC1 activity, our data suggest 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. A still unanswered question is what drives the small fraction of activated germinal center (GC) B cells to become long-lived quiescent memory B cells. We found here that a small population of GC-derived CD38intBcl6hi/intEfnb1+ cells with lower mTORC1 activity favored the memory B cell fate. Constitutively high mTORC1 activity led to defects in formation of the CD38intBcl6hi/intEfnb1+ cells; conversely, decreasing mTORC1 activity resulted in relative enrichment of this memory-prone population over the recycling-prone one. Furthermore, the CD38intBcl6hi/intEfnb1+ cells had higher levels of Bcl2 and surface BCR that, in turn, contributed to their survival and development. We also found that downregulation of Bcl6 resulted in increased expression of both Bcl2 and BCR. Given the positive correlation between the strength of T cell help and mTORC1 activity, our data suggest 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. |
| Author | Inoue, Takeshi Kawai, Chie Kawakami, Eiryo Kitamura, Toshio Yamashita, Kazuo Fukuyama, Hidehiro Sax, Nicolas Shinnakasu, Ryo Ise, Wataru Oki, Toshihiko Kurosaki, Tomohiro |
| AuthorAffiliation | 5 Division of Cellular Therapy, Advanced Clinical Research Center, and Division of Stem Cell Signaling, Center for Stem Cell Biology and Regeneration Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan 4 KOTAI Biotechnologies, Inc., Osaka, Japan 3 Artificial Intelligence Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan 2 Medical Sciences Innovation Hub Program, RIKEN, Kanagawa, Japan 6 Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan 1 Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan |
| AuthorAffiliation_xml | – name: 5 Division of Cellular Therapy, Advanced Clinical Research Center, and Division of Stem Cell Signaling, Center for Stem Cell Biology and Regeneration Medicine, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan – name: 6 Laboratory for Lymphocyte Differentiation, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan – name: 3 Artificial Intelligence Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan – name: 2 Medical Sciences Innovation Hub Program, RIKEN, Kanagawa, Japan – name: 1 Laboratory of Lymphocyte Differentiation, WPI Immunology Frontier Research Center, Osaka University, Osaka, Japan – name: 4 KOTAI Biotechnologies, Inc., Osaka, Japan |
| Author_xml | – sequence: 1 givenname: Takeshi orcidid: 0000-0002-9972-6105 surname: Inoue fullname: Inoue, Takeshi – sequence: 2 givenname: Ryo orcidid: 0000-0002-5369-3424 surname: Shinnakasu fullname: Shinnakasu, Ryo – sequence: 3 givenname: Chie orcidid: 0000-0001-5883-2377 surname: Kawai fullname: Kawai, Chie – sequence: 4 givenname: Wataru orcidid: 0000-0003-0457-3386 surname: Ise fullname: Ise, Wataru – sequence: 5 givenname: Eiryo orcidid: 0000-0001-9955-4342 surname: Kawakami fullname: Kawakami, Eiryo – sequence: 6 givenname: Nicolas orcidid: 0000-0003-3241-4737 surname: Sax fullname: Sax, Nicolas – sequence: 7 givenname: Toshihiko orcidid: 0000-0001-9083-3126 surname: Oki fullname: Oki, Toshihiko – sequence: 8 givenname: Toshio orcidid: 0000-0001-7855-1767 surname: Kitamura fullname: Kitamura, Toshio – sequence: 9 givenname: Kazuo orcidid: 0000-0002-0085-2057 surname: Yamashita fullname: Yamashita, Kazuo – sequence: 10 givenname: Hidehiro orcidid: 0000-0002-6457-0630 surname: Fukuyama fullname: Fukuyama, Hidehiro – sequence: 11 givenname: Tomohiro orcidid: 0000-0002-6352-304X surname: Kurosaki fullname: Kurosaki, Tomohiro |
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| Title | Exit from germinal center to become quiescent memory B cells depends on metabolic reprograming and provision of a survival signal |
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