Biology subjects

Dent, A. L.

Publications and source records attributed to Dent, A. L..

5 recordsLinked to original sources

bioRxiv2022

Nuclear proteins acquiring Germinal Center B cells are specifically suppressed by follicular regulatory T cells.

Follicular regulatory T cells (Tfrs) restrict development of autoantibodies and autoimmunity while supporting high-affinity foreign antigen-specific humoral response. However, whether Tfrs can directly repress germinal center (GC) B cells that acquire auto-antigens is unclear. Moreover, TCR specificity of Tfrs to self-antigens is not known. Our study suggests that nuclear proteins contain antigens specific to Tfrs. Targeting of these proteins to antigen-specific B cells triggers rapid accumulation of Tfrs with immunosuppressive characteristics. Tfrs then exert negative regulation of GC B cells with predominant inhibition of the nuclear protein-acquiring GC B cells, suggesting an important role of direct cognate Tfr-GC B cells interactions for the control of effector B cell response.

immunology↗

bioRxiv2021

STAT3 expression in dendritic cells protects mice from colitis by a gut microbiome-dependent mechanism

An imbalance in gut homeostasis results in local and systemic pathogenesis. It is still not well-understood how the immune system interacts with the gut microbiome and maintains a delicate balance. Here, we utilized a mouse model in which STAT3 expression is deleted in CD11c+ (i.e., dendritic) cells (STAT3 cKO); these mice developed an ulcerative colitis-like disease, colon carcinoma and myelodysplastic syndrome-like disease. Circulating IgE levels in STAT3 cKO mice were significantly elevated. The gut microbiome was indispensable for the observed pathogenesis, as treatment with broad-spectrum antibiotics or cross-fostering STAT3 cKO pups with mothers harboring a different microbiome prevented disease development. Gut microbiome analyses suggested that decreased commensal bacteria and increased pathogenic bacteria most likely contributed to disease. Our data suggest that STAT3 controls the manifestation of inflammation in the gut caused by the microbiome. Therefore, we conclude that a deficiency of STAT3 in DCs is sufficient to trigger uncontrolled inflammation and the development of inflammatory bowel disease.

immunology↗

bioRxiv2020

Broadly reactive influenza antibodies are not limited by germinal center competition with high affinity antibodies

Enhancing the generation of broadly reactive influenza antibodies is a pertinent goal towards developing a universal influenza vaccine. While antibodies that bind conserved influenza epitopes have been identified in humans, the frequency of these antibodies is typically very low. The predominant theory is that antibodies specific for conserved influenza epitopes are limited in germinal centers by competition with high affinity antibodies specific for the variable region of the virus. Here, we show that reducing germinal center formation and removing competition with high affinity antibodies was not sufficient to increase broadly reactive influenza antibodies or enhance protection against distinct influenza subtypes. These data disprove the prevailing hypothesis that broadly reactive influenza antibodies are rare due to competition in germinal centers. Additionally, levels of IgM antibodies specific for the variable region of HA persisted in mice in the absence of germinal centers, further demonstrating that immunodominance can be established independent of germinal centers. Our data also highlight the protective capacity of germinal center-independent IgM antibodies, which are not typically considered when testing correlates of protection, and offer an alternate target for delivering a universal influenza vaccine. IMPORTANCEIt is estimated that 250,000 - 650,000 individuals worldwide die each year from seasonal influenza infections. Current vaccines provide little protection against newly emerging strains. Thus, considerable effort is focused on enhancing the generation of broadly reactive influenza antibodies in order to develop a universal influenza vaccine. However, broadly reactive antibodies are rare and the factors that limit their generation are not completely understood. Our data disprove the prevailing hypothesis that broadly reactive influenza antibodies are rare due to completion in the germinal centers with antibodies to the variable HA head. Understanding the factors limiting antibodies specific for conserved regions of the influenza virus is imperative for developing a universal vaccine, which could potentially circumvent a global pandemic

immunology↗

bioRxiv2019

Allergen-induced airway inflammation and Th2 cell development requires Blimp-1

A Th2 immune response is central to allergic airway inflammation, which afflicts millions worldwide. However, the mechanisms that augment GATA3 expression in an antigen-primed developing Th2 cell are not well understood. Here, we describe an unexpected role for Blimp-1, a transcriptional repressor that constrains autoimmunity, as an upstream promoter of GATA3 expression that is critical for Th2 cell development in the lung, but dispensable for TFH function and IgE production. Mechanistically, Blimp-1 acts through Bcl6, which is necessary to drive GATA3 expression. Surprisingly, the anti-inflammatory cytokine IL-10, but not the pro-inflammatory cytokines IL-6 or IL-21, is required via STAT3 activation to upregulate Blimp-1 and promote Th2 cell development. These data reveal a hitherto unappreciated role for an IL-10-STAT3-Blimp-1 circuit as an initiator of an inflammatory Th2 response in the lung to allergens. Thus, Blimp-1 in a context-dependent fashion can drive inflammation by promoting rather than terminating effector T cell responses. SummaryThe transcriptional repressor Blimp-1 acts via a pro-inflammatory IL-10-STAT3 axis as a critical positive regulator of Th2 cells in the lung in response to allergens driving pathophysiology associated with asthma disease.

immunology↗

bioRxiv2019

Increased Th1 bias in memory T cells corresponds with protection from reinfection in Plasmodium infection, and is regulated by T cell-intrinsic STAT3

Hybrid Th1/Tfh cells (IFN-{gamma}+IL-21+CXCR5+) predominate in response to persistent infections; however, molecular regulation of their function is poorly defined. In infection with Plasmodium spp, an IFN-{gamma}+ T helper-1 (Th1) response controls initial parasitemia, while antibody and IL-21+CXCR5+ T follicular helper (Tfh) function effect final clearance. Here, we found that CD4-intrinsic Bcl6, Blimp-1 and STAT3 all regulate T-bet expression, which controls IFN-{gamma} expression. While Bcl6 and Blimp-1 regulate the level of CXCR5, only T-bet and STAT3 affected the functional bias of the Th1/Tfh phenotype. Infected mice with STAT3-deficient T cells produced less antibody, and more IFN-{gamma}+IL-21-CXCR5lo T cells, significantly increasing protection from re-infection. Conversely, reduced Th1 bias in re-infected T-bet KO was reflected in prolonged secondary parasitemia. In summary, each feature of hybrid Th1/Tfh population in Plasmodium infection is uniquely regulated and the cytokine bias of memory T cells can be modified to enhance the effectiveness of the response.

immunology↗