Abstract
B cell clones compete for entry into and dominance within germinal centers (GC), where the highest affinity BCRs are selected. However, diverse and low affinity B cells can enter and reside in GCs for extended periods. To reconcile these observations, we hypothesized 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 previously showed that NUR77 expression scales with antigen stimulation and restrains B cell expansion when T cell help is limiting. Here we show that, although NUR77 is dispensable for regulating GC size when GC are elicited in a largely clonal manner, it serves to curb immunodominance under conditions where diverse clonal populations must compete for a constrained niche. Moreover, this is independent of B cell precursor frequency and reflects, at least in part, a B cell-intrinsic role for NUR77. We propose that this is important to preserve early B cell 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
We demonstrated that NUR77 limits both proliferation and survival of B cells following B cell receptors (BCRs) stimulation (Figure 1B) (Tan et al, 2020; Tan et al, 2019)
Is CD86 overinduced in the absence of NUR77 at early time points, but this difference increases with time and scales with intensity of BCR 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)
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