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Helmholtz Munich I Daniela Barreto

Physiological Basis Of The Mature B Lymphocyte Plasticity Discovered

Featured Publication, LHI,

A new study led by Helmholtz Munich scientists Ursula Zimber-Strobl and Lothar J. Strobl sheds light on the intricate pathways of B-lymphocyte development during adaptive immune responses. The study, published in Nature Communications, reveals that after antigenic stimulation Notch2 signaling plays a crucial role in determining the fate of the activated B cells. The findings hold promise for refining vaccination approaches and advancing therapies in autoimmune diseases.

B-lymphocytes comprise a part of the adaptive immune system, which is responsible for the establishment of an antigen specific response to infections. They develop in the bone marrow and leave it as transitional B cells to finally mature in the spleen. The two main mature B lymphocyte populations, the Follicular and the Marginal Zone B cells (FoBs and MZBs), are thought to derive from a common precursor, the transitional T2 cells. Three years ago, a team of researchers around Helmholtz Munich scientists Ursula Zimber-Strobl and Lothar J. Strobl could show in a study published in Nature Communications, that also mature FoBs can completely convert to a MZB phenotype if they receive signaling by the Notch2 transmembrane receptor. However, at that time the underlying physiological conditions for this lineage conversion were completely unknown.

Unraveling B-Lymphocyte Development

In a follow-up paper, also published in Nature Communications, the scientists have now been able to show that, as part of a T cell-dependent immune response, the primarily activated FoB cells take different developmental routes depending on the strength of the Notch2 signal induced in the process. Cells with a turned off Notch2 signal enter the Germinal Center reaction to enhance B cell receptor affinity and to accomplish immunoglobulin class switching to give rise to memory B cells and high affinity plasma cells. Cells with an ongoing Notch2 signal develop – dependent on their IRF4 levels – either (high IRF4 levels) to extrafollicular low affinity IgM producing plasmablasts or (mid IRF4 levels) to MZB cells.

Implications for Vaccination Strategies

Thus, a T cell-dependent immune response appears to protect the organism on an even broader front than previously assumed. The results may also have implications for age-appropriate vaccinations: Infants exhibit almost exclusively naive MZBs, and older people have a MZB pool with greatly reduced clonality. As a result, they lack the first line defense against blood-borne pathogens and are therefore very susceptible to bacterial infections. Adapting vaccination strategies in the light of the new findings could potentially increase the proportion of antigen specific MZBs in young children and the elderly.

“This publication and our ongoing studies on the development of mature B lymphocyte populations will allow a more precise understanding of the role of MZBs and can provide the basis for more adapted vaccination strategies and improved therapies, e.g. in the area of autoimmune diseases.” says Lothar Strobl, the last author of the paper.


Original publication

Notch2 controls developmental fate choices between germinal center and marginal zone B cells upon immunization. Tea Babushku, Markus Lechner, Stefanie Ehrenberg, Ursula Rambold, Marc Schmidt-Supprian, Andrew J. Yates, Sanket Rane, Ursula Zimber-Strobl & Lothar J. Strobl. Nat. Commun. 2024. doi: 10.1038/s41467-024-46024-1


Lothar J. Strobl

Group Leader