Journal Article

CBirTox is a selective antigen-specific agonist of the Treg-IgA-microbiota homeostatic pathway

Elson, Charles O., Katz, Jannet, Alexander, Katie L.

2017

Overview

Cultivating an environment of mutualism between host cells and the microbiota is vital, and dysregulation of this relationship is associated with multiple immune disorders including metabolic and skin diseases, asthma, allergy, and Inflammatory Bowel Disease (IBD). One prominent mechanism for maintaining homeostasis is the protective regulatory T cell (Treg)- Immunoglobulin A (IgA) pathway toward microbiota antigens, in which Tregs maintain homeostasis and provide critical survival factors to IgA+ B cells. In order to amplify the Treg-IgA pathway, we have generated a fusion protein, CBirTox, comprised of a portion of the carboxy terminus of CBir1, a microbiota flagellin, genetically coupled to Cholera Toxin B subunit (CTB) via the A2 linker of CT. Both dendritic cells (DCs) and B cells pulsed with CBirTox selectively induced functional CD4+Foxp3+ Tregs in vitro, and CBirTox augmented CD4+Foxp3+ cell numbers in vivo. The induced Foxp3 expression was independent of retinoic acid (RA) signaling but was inhibited by neutralization of TGF-β. CBirTox treatment of B cells downregulated mammalian target of rapamycin (mTOR) signaling. Furthermore, CBirTox-pulsed DCs induced substantial production of IgA from naïve B cells. Collectively these data demonstrate that CBirTox represents a novel approach to bolstering the Treg-IgA pathway at the host-microbiota interface.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Allergies / Animals / Anti-inflammatory agents / Antigen presentation / Antigen-Presenting Cells - metabolism / Antigens / Asthma / B-Lymphocytes - immunology / Biology and Life Sciences / CD4 antigen / Cell Line / Cell survival / Cholera / Cholera toxin / Cholera Toxin - metabolism / Cholera toxin B subunit / Cytokines / Dendritic cells / Dendritic Cells - immunology / Diabetes / Epitopes - immunology / Flagellin / Flagellin - agonists / Forkhead Transcription Factors - metabolism / Foxp3 protein / Fusion protein / Genomics / Health aspects / Homeostasis / Hypersensitivity / Immunoglobulin A / Immunoglobulin A - immunology / Immunology / Infections / Inflammation / Inflammatory bowel diseases / Intestine / Intestines / Lymphocytes / Lymphocytes B / Lymphocytes T / Medicine and Health Sciences / Metabolism / Mice, Inbred C57BL / Microbiota / Mutualism / Neutralization / Physiological aspects / Proteins / Public health / Rapamycin / Recombinant Fusion Proteins - metabolism / Regulation / Research and Analysis Methods / Retinoic acid / Signal Transduction / Signaling / Skin diseases / T cell receptors / T cells / T-Lymphocytes, Regulatory - immunology / TOR protein / TOR Serine-Threonine Kinases - metabolism / Toxin b / Toxins / Transforming Growth Factor beta - metabolism / Transplants & implants / Tretinoin - metabolism / Vibrio cholerae / Water-borne diseases / Waterborne diseases