Abstract
SUMMARYB cell clones compete for entry into and dominance within germinal centers (GCs), where the highest-affinity B cell receptors (BCRs) are selected. However, diverse and low-affinity B cells can enter and reside in GCs for extended periods. To reconcile these observations, we hypothesize that a negative feedback loop may operate within B cells to preferentially restrain high-affinity clones from monopolizing the early GC niche. Here, we report a role for the nuclear receptor NUR77/Nr4a1 in this process. We show that NUR77 expression scales with antigen stimulation and restrains B cell expansion. Although NUR77 is dispensable for regulating GC size when GCs are elicited in a largely clonal manner, it serves to curb immunodominance under conditions where diverse clonal populations must compete for a constrained niche. We propose that this is important to preserve early clonal diversity in order to limit holes in the post-immune repertoire and to optimize GC selection.
Highlights
Germinal centers (GCs) nurture the diversification, proliferation, and selection of high-affinity B cell clones
NUR77 regulates the expression of genes associated with T cell help and GC participation We previously showed, using a fluorescent reporter of Nr4a1 transcription (NUR77/Nr4a1-EGFP BAC Tg), that NUR77 expression scales with antigen receptor stimulation in B cells (Figure 1A) (Tan et al, 2020; Zikherman et al, 2012)
Is CD86 overinduced in the absence of NUR77 at early time points, but this difference increases with time and scales with intensity of B cell receptors (BCRs) stimulation (Figures S1B and S1C)
Summary
Germinal centers (GCs) nurture the diversification, proliferation, and selection of high-affinity B cell clones. Up to 100 different B cell clones can seed an individual GC (Tas et al, 2016) This early clonal diversity is considered essential for driving optimal competition as the GC reaction evolves; excessive early dominance of a single high-affinity clone compromises optimal affinity maturation and risks inappropriately focusing the immune response on a non-neutralizing target, creating holes in the repertoire that pathogens could exploit (Abbott and Crotty, 2020; Le et al, 2008; Mesin et al, 2016). We test whether the orphan nuclear receptor NUR77/Nr4a1 may restrain immunodominance in the early GC by mediating a negative feedback loop downstream of the B cell receptor (BCR)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
