Stromal Notch ligands foster lymphopenia-driven functional plasticity and homeostatic proliferation of naive B cells.

Autor:	Gómez Atria D; Division of Hematology/Oncology, Department of Medicine., Gaudette BT; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, and., Londregan J; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, and.; Immunology Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Kelly S; Division of Hematology/Oncology, Department of Medicine., Perkey E; Division of Hematology/Oncology, Department of Medicine.; Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, Michigan, USA., Allman A; Division of Hematology/Oncology, Department of Medicine., Srivastava B; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, and.; Immunology Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Koch U; EPFL, Lausanne, Switzerland., Radtke F; EPFL, Lausanne, Switzerland., Ludewig B; Medical Research Center, Kantonsspital St. Gallen, St. Gallen, Switzerland., Siebel CW; Department of Discovery Oncology, Genentech, South San Francisco, California, USA., Ryan RJ; Department of Pathology, University of Michigan, Ann Arbor, Michigan, USA., Robertson TF; Immunology Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Burkhardt JK; Immunology Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA., Pear WS; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, and.; Immunology Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Allman D; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, and.; Immunology Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania, USA., Maillard I; Division of Hematology/Oncology, Department of Medicine.; Immunology Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Jazyk:	angličtina
Zdroj:	The Journal of clinical investigation [J Clin Invest] 2022 Jul 01; Vol. 132 (13).
DOI:	10.1172/JCI158885
Abstrakt:	In lymphopenic environments, secondary lymphoid organs regulate the size of B and T cell compartments by supporting the homeostatic proliferation of mature lymphocytes. The molecular mechanisms underlying these responses and their functional consequences remain incompletely understood. To evaluate homeostasis of the mature B cell pool during lymphopenia, we turned to an adoptive transfer model of purified follicular B cells into Rag2-/- mouse recipients. Highly purified follicular B cells transdifferentiated into marginal zone-like B cells when transferred into Rag2-/- lymphopenic hosts but not into wild-type hosts. In lymphopenic spleens, transferred B cells gradually lost their follicular phenotype and acquired characteristics of marginal zone B cells, as judged by cell surface phenotype, expression of integrins and chemokine receptors, positioning close to the marginal sinus, and an ability to rapidly generate functional plasma cells. Initiation of follicular to marginal zone B cell transdifferentiation preceded proliferation. Furthermore, the transdifferentiation process was dependent on Notch2 receptors in B cells and expression of Delta-like 1 Notch ligands by splenic Ccl19-Cre+ fibroblastic stromal cells. Gene expression analysis showed rapid induction of Notch-regulated transcripts followed by upregulated Myc expression and acquisition of broad transcriptional features of marginal zone B cells. Thus, naive mature B cells are endowed with plastic transdifferentiation potential in response to increased stromal Notch ligand availability during lymphopenia.
Databáze:	MEDLINE
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