Long-Lasting T Cell-Independent IgG Responses Require MyD88- Mediated Pathways and Are Maintained by High Levels of Virus Persistence

ABSTRACT Many 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 re-sponses in the form of long-lived plasma cells andmemory B cells. We found that T cell-deficient (T cell receptor and chain [TCR] 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. TCRKOmice 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 defi-cient in CD4 T cells had a lower persisting virus load than TCRKOmice, and these mice had short-lived antiviral IgG re-sponses, suggesting that a high virus load is required to activate naive B cells continuously, andmaintain 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 re-ceptor (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 TCRKO/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. IMPORTANCE Lifelong 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 morbidi-ty/mortality in the severely immune compromised. Studying the multiple mechanisms that control viral persistence in a mous