Biology subjects

Bricker, K. N.

Publications and source records attributed to Bricker, K. N..

3 recordsLinked to original sources

bioRxiv2022

STAT3 signaling in B cells controls germinal center zone organization and recycling

Germinal centers (GCs), sites of antibody affinity maturation, are organized into dark (DZ) and light (LZ) zones. Here, we uncovered a B cell intrinsic role for STAT3 in GC DZ and LZ organization. Altered zonal organization of STAT3-deficient GCs dampened GC output of long-lived plasma cells (LL-PCs) but increased memory B cells (MBCs). Tfh-GC B cell interaction drive STAT3 tyrosine 705 and serine 727 phosphorylation in LZ B cells, facilitating their recycling into the DZ. An inducible system confirmed STAT3 is not involved in initiating or maintaining the GC but sustains GC zonal organization by regulating GC B cell recycling. RNAseq and ChIPseq analysis identified genes regulated by STAT3 that are critical for LZ cell recycling and transiting through the DZ proliferation and differentiation phases of the DZ. Thus, STAT3 signaling in B cells controls GC zone organization and recycling, and GC egress of LL-PCs, but negatively regulates MBC output. SummaryFike et al. describe a previously unrecognized mechanism by which B cell intrinsic STAT3 signaling controls the germinal center (GC) dark and light zone organization, GC B cell recycling, and GC output of long-lived plasma cells but negatively regulates memory B cells.

immunology↗

bioRxiv2022

Orai3 and Orai1 are essential for CRAC channel function and metabolic reprogramming in B cells

The essential role of store-operated Ca2+ entry (SOCE) through Ca2+ release-activated Ca2+ (CRAC) channels in T cells is well established. In contrast, the contribution of individual Orai isoforms to SOCE and their downstream signaling functions in B cells are poorly understood. Here, we demonstrate changes in expression of Orai isoforms in response to B cell activation. We show that Orai3 and Orai1 are essential components of native CRAC channels in B cells and are critical for primary B cell proliferation and survival. The combined loss of Orai1 and Orai3 strongly impairs SOCE, nuclear factor for activated T cells (NFAT) activation, mitochondrial respiration, glycolysis, and the metabolic reprogramming of B cells in response to antigenic stimulation. Our results clarify the molecular composition and cellular functions of SOCE in B lymphocytes.

immunology↗

bioRxiv2021

Context-dependent miR-21 regulation of TLR7-mediated autoimmune and foreign antigen driven antibody-forming cell and germinal center responses

MicroRNAs (miRNAs) are involved in healthy B cell responses and the loss of tolerance in systemic lupus erythematosus (SLE), though the role of many miRNAs remains poorly understood. Dampening miR-21 activity was previously shown to reduce splenomegaly and blood urea nitrogen levels in SLE-prone mice, but the detailed cellular responses and mechanism of action remains unexplored. Herein, using the TLR7 agonist imiquimod-induced SLE model, we observed that loss of miR-21 in Sle1b mice prevented the formation of plasma cells and autoantibody forming cells (AFC), without a significant effect on the magnitude of the germinal center (GC) response. We further observed reduced dendritic cell and monocyte numbers in the spleens of miR-21 deficient Sle1b (Sle1b.miR-21KO) mice that were associated with reduced interferon, proinflammatory cytokines, and effector CD4+ T cell responses. RNAseq analysis on B cells from Sle1b.miR-21KO mice revealed reduced activation and response to interferon and cytokine and target array analysis revealed modulation of numerous miR-21 target genes in response to TLR7 activation and type I interferon stimulation. Our findings in the B6.Sle1b.Yaa spontaneous model recapitulated the miR-21 role in TLR7-induced responses with an additional role in autoimmune GC and Tfh responses. Finally, immunization with T-dependent antigen revealed a role for miR-21 in foreign antigen driven GC and Ab, but not AFC responses. Our data suggest a potential multifaceted, context-dependent role for miR-21 in autoimmune and foreign antigen driven AFC and GC responses. Further study is warranted to delineate the cell-intrinsic requirements and mechanisms of miR-21 during infection and SLE development. Key PointsO_LImiR-21 has context dependent effects on AFC and GC responses C_LIO_LImiR-21 promotes TLR7-driven autoimmunity with activation of multiple B cell pathways C_LIO_LImiR-21 is required for optimal B cell responses to T-dependent foreign antigen C_LI

immunology↗