ABSTRACTMany viruses induce acute T cell-independent (TI) B cell responses due to their repetitive epitopes and the induction of innate cytokines. Nevertheless, T cell help is thought necessary for the development of long-lasting antiviral antibody responses in the form of long-lived plasma cells and memory B cells. We found that T cell-deficient (T cell receptor β and δ chain [TCRβδ] knockout [KO]) mice persistently infected with polyomavirus (PyV) had long-lasting antiviral serum IgG, and we questioned whether they could generate TI B cell memory. TCRβδ KO mice did not form germinal centers after PyV infection, lacked long-lived IgG-secreting plasma cells in bone marrow, and did not have detectable memory B cell responses. Mice deficient in CD4+T cells had a lower persisting virus load than TCRβδ KO mice, and these mice had short-lived antiviral IgG responses, suggesting that a high virus load is required to activate naive B cells continuously, and maintain the long-lasting serum IgG levels. Developing B cells in bone marrow encounter high levels of viral antigens, which can cross-link both their B cell receptor (BCR) and Toll-like receptors (TLRs), and this dual engagement may lead to a loss of their tolerance. Consistent with this hypothesis, antiviral serum IgG levels were greatly diminished in TCRβδ KO/MyD88−/−mice. We conclude that high persisting antigen levels and innate signaling can lead to the maintenance of long-lasting IgG responses even in the absence of T cell help.IMPORTANCELifelong control of persistent virus infections is essential for host survival. Several members of the polyomavirus family are prevalent in humans, persisting at low levels in most people without clinical manifestations, but causing rare morbidity/mortality in the severely immune compromised. Studying the multiple mechanisms that control viral persistence in a mouse model, we previously found that murine polyomavirus (PyV) induces protective T cell-independent (TI) antiviral IgG. TI antibody (Ab) responses are usually short-lived, but T cell-deficient PyV-infected mice can live for many months. This study investigates how protective IgG is maintained under these circumstances and shows that these mice lack both forms of B cell memory, but they still have sustained antiviral IgG responses if they have high levels of persisting virus and intact MyD88-mediated pathways. These requirements may ensure life-saving protection against pathogens even in the absence of T cells, but they prevent the continuous generation of TI IgG against harmless antigens.
B cells transiently exposed to antigen that return to quiescence respond to protein immunization similarly to naive B cells