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

Abstract

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

Tissue-resident CD4+T helper cells assist protective respiratory mucosal B and CD8+T cell memory responses

“…Purified antigens were biotinylated using an EZ-Link Sulfo-NHS-LCBiotinylation kit (Thermo Fisher Scientific) using a 1:1.3 M ratio of biotin to Ag. To make tetramers, biotinylated Ags were mixed with streptavidin–PE (PJ27S; ProZyme) at the ratio determined or at a 5 to 1 ratio using the biotin concentration provided by the manufacturer as described before 86 . Following a 30-min incubation on ice, unconjugated biotinylated Ag was often removed by several rounds of dilution and concentration using a 100 kDa Amicon Ultra (MilliporeSigma) or 300 kDa Nanosep centrifugal devices (Pall).…”

Protective Antibodies Against Human Parainfluenza Virus Type 3 (HPIV3) Infection

“…In anticipation of administering these antibodies in vivo , we confirmed that none bound to permeabilized HEp-2 cells ( Fig. 3f ), a common assessment of autoreactivity 28,29 .…”

Protective antibodies against human parainfluenza virus type 3 infection

“…In anticipation of administering these antibodies in vivo , we confirmed that none bound to permeabilized HEp-2 cells ( Figure 3d ), a common assessment of autoreactivity. 28 , 29 …”

“…In anticipation of administering these antibodies in vivo, we confirmed that none bound to permeabilized HEp-2 cells (Figure 3d), a common assessment of autoreactivity. 28,29 We next performed cross-competition binding experiments to gauge the antigenic sites on HPIV3 preF allowing for neutralization. Three of these five new neutralizing mAbs (PI3-E12, -A3, and -B5) fully competed with each other and the previously described antibody PIA174 (Figure 4a).…”