Acquisition of innate B cell properties and generation of autoreactive IgA antibodies by follicular B cells during homeostatic proliferation

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 <i>Rag2^-/-</i> hosts, we here show that not only innate B cells - MZBs and B1a cells - 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 <i>in vitro</i>, 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.