{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T14:14:40Z","timestamp":1783606480520,"version":"3.55.0"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T00:00:00Z","timestamp":1737504000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The physiologic process of homeostatic proliferation serves to restore the pool of peripheral lymphocytes in response to lymphopenia. However, functional changes in B cell responses during homeostatic proliferation are still only insufficiently characterized. Mature peripheral B cells consist of functionally distinct B cell subsets, such as adaptive follicular B cells (FoBs) and the innate B cell subsets, marginal zone B cells (MZBs) and B1a B cells. During homeostatic proliferation, B cells undergo antigen-independent clonal expansion and differentiation into antibody-producing plasma cells (PCs). However, it is still largely unknown which B cell lineages are involved in the formation of antibodies in response to lymphopenia and what functional properties these antibodies have. Employing adoptive transfer of different mature B cell subsets into lymphopenic <jats:italic>Rag2<jats:sup>-\/-<\/jats:sup><\/jats:italic> hosts, we here show that not only innate B cells \u2013 MZBs and B1a cells \u2013 but also adaptive FoBs were capable to differentiate into PCs and to produce IgM and class-switched IgA serum antibodies in a T cell-independent fashion during homeostatic proliferation. In light of the poor reactivity of FoBs to innate stimulation <jats:italic>in vitro<\/jats:italic>, the observed high expansion capacity of FoBs, their sustained repopulation of lymphoid and intestinal organs and their particularly prominent ability to induce class-switched auto-\/polyreactive IgA antibodies in this antigen- and T cell-independent system was rather unexpected. These properties, which are more typical for innate B cells, were associated with a striking plasticity of FoBs that transdifferentiate into MZB-like cells under lymphopenic conditions. Together, our study indicates that the reconstitution of antibodies in response to lymphopenia-induced homeostatic B cell proliferation is mainly elicited by innate MZB-like B cell responses via antigen- and T cell-independent pathways resulting in the selection of autoreactive IgA antibodies. In addition, our data point to the pathogenic potential of the conversion of conventional adaptive B cells, which are the most common population of mature B cells, into innate-like B cells and the production of autoreactive IgA antibodies during homeostatic proliferation. This process could also manifest as clinical complication of therapy-induced lymphopenia in the context of transplantation and cancer in human patients.<\/jats:p>","DOI":"10.3389\/fimmu.2025.1506628","type":"journal-article","created":{"date-parts":[[2025,1,22]],"date-time":"2025-01-22T05:19:59Z","timestamp":1737523199000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Acquisition of innate B cell properties and generation of autoreactive IgA antibodies by follicular B cells during homeostatic 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