Cross-Reactivity with Self-Antigen Tunes the Functional Potential of Naive B Cells Specific for Foreign Antigens

Upon antigen exposure, naïve B cells expressing B cell receptors (BCR) able to bind antigen can undergo robust proliferation and differentiation that can result in the production of antibody-secreting and memory B cells. The factors determining whether an individual naïve B cell will proliferate following antigen encounter remains unclear. In this study, we found that polyclonal naïve murine B cell populations specific for a variety of foreign antigens express high levels of the orphan nuclear receptor Nur77, which is known to be up-regulated downstream of BCR signaling as a result of cross-reactivity with self-antigens in vivo. Similarly, a fraction of naïve human B cells specific for clinically-relevant antigens derived from respiratory syncytial virus (RSV) and HIV-1 also exhibited an IgM(LOW) IgD(+) phenotype, which is associated with self-antigen cross-reactivity. Functionally, naïve B cells expressing moderate levels of Nur77 are most likely to proliferate in vivo following antigen injection. Together, our data indicate that BCR cross-reactivity with self-antigen is a common feature of populations of naïve B cells specific for foreign antigens and a moderate level of cross-reactivity primes individual cells for optimal proliferative responses following antigen exposure.