Negative feedback by NUR77/Nr4a1 restrains B cell clonal dominance during early T-dependent immune responses

Abstract

Brooks et al. define a new role for NUR77in regulating clonal B cell competition during early humoral immune responses to immunization. The authors reveal that NUR77 is dispensable for germinal center size, but it serves to curb immunodominance when B cells must compete against each other into a limited niche.

NR4A nuclear receptors in T and B lymphocytes: Gatekeepers of immune tolerance*

“…However, we were unable to identify an advantage for Nr4a1 -/mice in mounting responses to T-dependent immunogens like NP-KLH either in terms of GC size, antibody titer, or affinity maturation. 13,14 We instead found that the NR4A family regulates B cell responses specifically in competitive settings when T cell help is limiting, and this advantage was eliminated by excess T cell help (Figure 3B,C). 13 Since NR4A expression is induced in proportion to the strength of Ag stimulation, negative regulation by the NR4A family should also scale with Ag stimulation.…”

“…This would limit immunodominance of high‐affinity clones and permit greater expansion of lower affinity clones. To test this hypothesis, we sought to create a novel set of immunogens that would titrate relative immunodominance between a pair of competing B cell specificities by varying the conjugation ratio of NP to OVA protein 14 . In Nr4a1 –/– mice (and to a lesser extent in mb1‐cre Nr4a1 fl/fl mice), immunodominant B cell clones outcompete subdominant clones to a greater extent than in WT mice, regardless of the clonal hierarchy imposed by a given immunogen 14 .…”

“…For several years, our laboratory has been interested in the dynamic induction of NR4A expression in lymphocytes triggered by antigen encounter, and we have exploited a reporter of Nr4a1 transcription to link antigen stimulation with lymphocyte behavior on a single‐cell level in a variety of settings 7‐11 . We have gone on to explore how the NR4A family in turn modulates B cell responses to both acute and chronic antigen encounter and identified regulatory roles in both contexts with implications for B cell tolerance and for B cell clonal competition during T‐dependent immune responses 12‐15 . Most recently, we have taken advantage of both conditional genetic strategies and bone marrow chimeras to untangle cell autonomous and cell non‐autonomous contributions of the NR4A family to normal immune homeostasis 16 …”

“…[7][8][9][10][11] We have gone on to explore how the NR4A family in turn modulates B cell responses to both acute and chronic antigen encounter and identified regulatory roles in both contexts with implications for B cell tolerance and for B cell clonal competition during T-dependent immune responses. [12][13][14][15] Most recently, we have taken advantage of both conditional genetic strategies and bone marrow chimeras to untangle cell autonomous and cell non-autonomous contributions of the NR4A family to normal immune homeostasis. 16 The role of the NR4A family in thymic-negative selection and peripheral T cell responses has been recently reviewed.…”

Microbubbles for improved nucleic acid extraction in wastewater samples for viral RNA detection

“…Microbubbles have been used for many applications, including cell isolations—more commonly known as Buoyancy Activated Cell Sorting (Akadeum Life Sciences, 2020; McNaughton et al, 2018; Jeon, D. & McNeel, D., 2022; Brooks et al, 2021), dead cell removal (Akadeum Life Sciences, 2022; McNaughton et al, 2018), cell therapy (Snow et al, 2022) and nucleic acid extractions from saliva (Akadeum Life Sciences, 2021). As detailed above, we have demonstrated a new protocol and application for microbubbles: viral nucleic acid extraction from wastewater using microbubbles.…”