Julie Zikherman, University of California, San Francisco
How are spurious responses to self-antigens normally suppressed in B cells? The Nr4a1, 2, and 3 genes encode a small family of orphan nuclear receptors Nur77, Nurr1, and Nor1 respectively, that share significant structural similarities in their DNA and ligand binding domains, and functional homology in vivo. Nr4a1-3 are among a small set of primary response genes (PRGs) that are rapidly and robustly induced in response to antigen receptor stimulation in lymphocytes, yet little is known about their function in B cells. Here we present data to suggest that Nur77 (Nr4a1) selectively restrains self-reactive B cells.
We have identified independent roles for Nur77 in mediating both BCR-induced proliferation and cell death, in part by restraining transcription of other PRGs. Indeed, deletion of Nr4a1 is sufficient to markedly amplify T-independent immune responses.
In addition to upregulation by acute BCR stimulation, we have recently shown that Nur77 is also upregulated by chronic antigen stimulation in naturally occurring, highly self-reactive B-1a cells. Deletion of Nur77 in B-1a cells results in a marked expansion of IgM plasma cells and increased natural IgM serum Ab under steady-state conditions.
We have also identified selective upregulation of Nur77 expression in autoreactive B cells from two mouse models of B cell anergy: VH3H9 heavy chain (HC) and Ig-HEL / soluble-HEL. We find that Nur77 expression is largely dispensible for receptor editing, deletion, IgM downregulation and anergic BCR signaling by self-reactive B cells. However, we identify a role for Nur77 in restraining survival of chronically antigen-stimulated B cells. Moreover, we find that Nur77-deficiency is sufficient to break B cell tolerance in VH3H9 HC mice.
We thus propose that Nur77 mediates negative feedback downstream of robust antigen stimulation in B cells, and is upregulated in response to chronic antigen stimulation where it imposes a novel layer of tolerance by restricting the survival of self-reactive B cells.
PDF Flyer: zikherman_v3.pdf