B-1a cells acquire their unique characteristics by bypassing the pre-BCR selection stage

Jason B. Wong; Susannah L. Hewitt; Lynn M. Heltemes-Harris; Malay Mandal; Kristen Johnson; Klaus Rajewsky; Sergei B. Koralov; Marcus R. Clark; Michael A. Farrar; Jane A. Skok

doi:10.1038/s41467-019-12824-z

B-1a cells acquire their unique characteristics by bypassing the pre-BCR selection stage

Jason B. Wong, Susannah L. Hewitt, Lynn M. Heltemes-Harris, Malay Mandal, Kristen Johnson, Klaus Rajewsky, Sergei B. Koralov, Marcus R. Clark, Michael A. Farrar, Jane A. Skok

Laboratory Medicine and Pathology

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

Abstract

B-1a cells are long-lived, self-renewing innate-like B cells that predominantly inhabit the peritoneal and pleural cavities. In contrast to conventional B-2 cells, B-1a cells have a receptor repertoire that is biased towards bacterial and self-antigens, promoting a rapid response to infection and clearing of apoptotic cells. Although B-1a cells are known to primarily originate from fetal tissues, the mechanisms by which they arise has been a topic of debate for many years. Here we show that in the fetal liver versus bone marrow environment, reduced IL-7R/STAT5 levels promote immunoglobulin kappa gene recombination at the early pro-B cell stage. As a result, differentiating B cells can directly generate a mature B cell receptor (BCR) and bypass the requirement for a pre-BCR and pairing with surrogate light chain. This ‘alternate pathway’ of development enables the production of B cells with self-reactive, skewed specificity receptors that are peculiar to the B-1a compartment. Together our findings connect seemingly opposing lineage and selection models of B-1a cell development and explain how these cells acquire their unique properties.

Original language	English (US)
Article number	4768
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-12824-z
State	Published - Dec 1 2019

Bibliographical note

Funding Information:
The authors would like to thank the NYU Flow Cytometry and Cell Sorting Center as well as the NYU Genome Technology Center, both of which are supported in part by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center. We would like to thank Meinrad Busslinger and Taras Kreslavsky (Research Institute of Molecular Pathology (IMP)) for suggesting the transitional B-1a cell experiment. In addition, we would like to thank the Skok lab for discussions on the study. J.A.S. is supported by NIH grants R35GM122515. J.B.W. was previously supported by the T32 CA009161 training grant (Levy) and the 2T32 AI100853-06 (Reizis) training grant. S.L.H. was supported by an American Society of Hematology (ASH) Scholar Award and by a Molecular Oncology and Immunology Training Grant NIH T32. M.A.F. is supported by NIH grants CA151845 and CA154998.

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title = "B-1a cells acquire their unique characteristics by bypassing the pre-BCR selection stage",

abstract = "B-1a cells are long-lived, self-renewing innate-like B cells that predominantly inhabit the peritoneal and pleural cavities. In contrast to conventional B-2 cells, B-1a cells have a receptor repertoire that is biased towards bacterial and self-antigens, promoting a rapid response to infection and clearing of apoptotic cells. Although B-1a cells are known to primarily originate from fetal tissues, the mechanisms by which they arise has been a topic of debate for many years. Here we show that in the fetal liver versus bone marrow environment, reduced IL-7R/STAT5 levels promote immunoglobulin kappa gene recombination at the early pro-B cell stage. As a result, differentiating B cells can directly generate a mature B cell receptor (BCR) and bypass the requirement for a pre-BCR and pairing with surrogate light chain. This {\textquoteleft}alternate pathway{\textquoteright} of development enables the production of B cells with self-reactive, skewed specificity receptors that are peculiar to the B-1a compartment. Together our findings connect seemingly opposing lineage and selection models of B-1a cell development and explain how these cells acquire their unique properties.",

author = "Wong, {Jason B.} and Hewitt, {Susannah L.} and Heltemes-Harris, {Lynn M.} and Malay Mandal and Kristen Johnson and Klaus Rajewsky and Koralov, {Sergei B.} and Clark, {Marcus R.} and Farrar, {Michael A.} and Skok, {Jane A.}",

note = "Funding Information: The authors would like to thank the NYU Flow Cytometry and Cell Sorting Center as well as the NYU Genome Technology Center, both of which are supported in part by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center. We would like to thank Meinrad Busslinger and Taras Kreslavsky (Research Institute of Molecular Pathology (IMP)) for suggesting the transitional B-1a cell experiment. In addition, we would like to thank the Skok lab for discussions on the study. J.A.S. is supported by NIH grants R35GM122515. J.B.W. was previously supported by the T32 CA009161 training grant (Levy) and the 2T32 AI100853-06 (Reizis) training grant. S.L.H. was supported by an American Society of Hematology (ASH) Scholar Award and by a Molecular Oncology and Immunology Training Grant NIH T32. M.A.F. is supported by NIH grants CA151845 and CA154998. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

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doi = "10.1038/s41467-019-12824-z",

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AU - Hewitt, Susannah L.

AU - Heltemes-Harris, Lynn M.

AU - Mandal, Malay

AU - Johnson, Kristen

AU - Rajewsky, Klaus

AU - Koralov, Sergei B.

AU - Clark, Marcus R.

AU - Farrar, Michael A.

AU - Skok, Jane A.

N1 - Funding Information: The authors would like to thank the NYU Flow Cytometry and Cell Sorting Center as well as the NYU Genome Technology Center, both of which are supported in part by the Cancer Center Support Grant P30CA016087 at the Laura and Isaac Perlmutter Cancer Center. We would like to thank Meinrad Busslinger and Taras Kreslavsky (Research Institute of Molecular Pathology (IMP)) for suggesting the transitional B-1a cell experiment. In addition, we would like to thank the Skok lab for discussions on the study. J.A.S. is supported by NIH grants R35GM122515. J.B.W. was previously supported by the T32 CA009161 training grant (Levy) and the 2T32 AI100853-06 (Reizis) training grant. S.L.H. was supported by an American Society of Hematology (ASH) Scholar Award and by a Molecular Oncology and Immunology Training Grant NIH T32. M.A.F. is supported by NIH grants CA151845 and CA154998. Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - B-1a cells are long-lived, self-renewing innate-like B cells that predominantly inhabit the peritoneal and pleural cavities. In contrast to conventional B-2 cells, B-1a cells have a receptor repertoire that is biased towards bacterial and self-antigens, promoting a rapid response to infection and clearing of apoptotic cells. Although B-1a cells are known to primarily originate from fetal tissues, the mechanisms by which they arise has been a topic of debate for many years. Here we show that in the fetal liver versus bone marrow environment, reduced IL-7R/STAT5 levels promote immunoglobulin kappa gene recombination at the early pro-B cell stage. As a result, differentiating B cells can directly generate a mature B cell receptor (BCR) and bypass the requirement for a pre-BCR and pairing with surrogate light chain. This ‘alternate pathway’ of development enables the production of B cells with self-reactive, skewed specificity receptors that are peculiar to the B-1a compartment. Together our findings connect seemingly opposing lineage and selection models of B-1a cell development and explain how these cells acquire their unique properties.

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B-1a cells acquire their unique characteristics by bypassing the pre-BCR selection stage

Abstract

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