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

• Published in: The Journal of clinical investigation 2022-07, Vol.132 (13), p.1-15
• Main Authors: Gómez Atria, Daniela, Gaudette, Brian T, Londregan, Jennifer, Kelly, Samantha, Perkey, Eric, Allman, Anneka, Srivastava, Bhaskar, Koch, Ute, Radtke, Freddy, Ludewig, Burkhard, Siebel, Christian W, Ryan, Russell Jh, Robertson, Tanner F, Burkhardt, Janis K, Pear, Warren S, Allman, David, Maillard, Ivan
• Format: Article
• Language: English
• Subjects: Adaptation (Physiology); Adoptive transfer; B cells; Biomedical research; CCL19 protein; Cell division; Cell proliferation; Cell surface; Chemokine receptors; DELTA protein; Functional plasticity; Gene expression; Genotype & phenotype; Health aspects; Homeostasis; Homeostatic plasticity; Immunology; Integrins; Ligands; Lymphocytes; Lymphocytes B; Lymphocytes T; Lymphocytopenia; Lymphopenia; Molecular modelling; Myc protein; Phenotypes; Physiological aspects; Plasma cells; RAG2 protein; Spleen; Stromal cells; T cell receptors
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI158885

In lymphopenic environments, secondary lymphoid organs regulate the size of B and T-cell compartments by supporting 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-like1 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, naïve mature B-cells are endowed with plastic transdifferentiation potential in response to increased stromal Notch ligand availability during lymphopenia.