Immunology Faculty Member - Talal Chatila, MD, PhD

Talal Chatila, MD, PhD

Professor of Pediatrics

Boston Children's Hospital
Karp Family Building, Room 10-214
1 Blackfan St.
Boston, MA 02115
Tel: 617-919-3529
Fax: 617-730-0528
Email: talal.chatila@childrens.harvard.edu



Our studies aim to elucidate the role of T regulatory (Treg) cells in peripheral immunological tolerance. We are particularly interested in identifying novel genetic pathways that control Treg cell function and are targeted by mutations in human diseases. We are also interested in elucidating mechanisms by which of Treg cells maintain mucosal tolerance and how their breakdown fosters inflammatory diseases, particularly food allergy and asthma.
Our studies on mechanisms by which Treg cells maintain mucosal tolerance led to the identification of Treg cells as microbial sensors that respond to microbiota signals delivered via the Toll-like receptor-coupled adaptor MyD88 to regulate the interaction of the adaptive immune response with the commensal flora (1). Dysfunction of the latter pathway maybe relevant to several disorders of intestinal mucosal inflammation such as seen in Treg cell deficiency diseases (2).
We have extended our studies on Treg cells in mucosal tolerance to common allergic disorders including food allergy, which is characterized by the breakdown in tolerance to normally innocuous nutrients. Our studies on the causes of tolerance breakdown in food allergy have identified Treg cells as the target of subversion by the intense pro-allergic environment in the gut of food allergic subjects, which renders the Treg cells pro-allergic (3, 4). Reprogramming the Treg cells by antagonizing pro-allergic cytokines and pathways offers promising therapeutic strategies for re-establishing oral tolerance in subjects with food allergies and asthma. We are currently pursuing proof of concept studies using preclinical mouse models that we have developed in our laboratory. We aim to translate these studies into clinical trials in the near future.
Our studies on the fundamental biology of Treg cells have led to the recent elucidation of the role of inflammatory signals delivered via the Notch receptor pathway in disrupting Treg cell function (5). Intense, aberrant activation of Notch signaling in Treg cells in graft versus host disease plays a prominent role in the immunopathology of this disorder. Notch signaling in Treg cells is also highly relevant to mechanisms by which environmental pollutants such as particulate matter (PM) generated by combustion engines promote airway inflammation. We have shown that PM activates a signaling pathway involving the Aryl hydrocarbon receptor and the Notch ligand jagged 1 to augment allergic airway inflammation (6). Blockade of Notch receptor signaling in Treg cells may offer therapeutic potential in these and other inflammatory and autoimmune diseases.
Finally, we have complemented our investigations on the role of Treg cells in peripheral tolerance in genetic animal models and common inflammatory disorders with studies that focus on gene discovery in human subjects with heritable immune dysregulatory diseases and Treg cell deficiency. Our previous studies have identified
FOXP3, IL2RA and DOCK8 as targets of mutations in human subjects that cause distinct autoimmune and immunodysregulatory disorders in affected human subjects. Our latest studies have extended these genetic networks to include LRBA, encoding LPS-responsive Beige-like Anchor protein, as a cause of Treg cell deficiency and autoimmunity in human subjects (7). The mechanisms by which mutations affecting these genes disrupt tolerance remains the subject of ongoing investigations by our group.



Last Update: 3/9/2016



Publications

1. Wang, S., Charbonnier, L.M., Noval Rivas, M., Georgiev, P., Li, N., Gerber, G., Bry, L., and Chatila, T.A. 2015. MyD88 Adaptor-Dependent Microbial Sensing by Regulatory T Cells Promotes Mucosal Tolerance and Enforces Commensalism. Immunity 43:289-303.
2. Rivas, M.N., Koh, Y.T., Chen, A., Nguyen, A., Lee, Y.H., Lawson, G., and Chatila, T.A. 2012. MyD88 is critically involved in immune tolerance breakdown at environmental interfaces of Foxp3-deficient mice.
J Clin Invest 122:1933-1947.
3. Noval Rivas, M., Burton, O.T., Wise, P., Charbonnier, L.M., Georgiev, P., Oettgen, H.C., Rachid, R., and Chatila, T.A. 2015. Regulatory T Cell Reprogramming toward a Th2-Cell-like Lineage Impairs Oral Tolerance and Promotes Food Allergy.
Immunity 42:512-523.
4. Burton, O.T., Noval Rivas, M., Zhou, J.S., Logsdon, S.L., Darling, A.R., Koleoglou, K.J., Roers, A., Houshyar, H., Crackower, M.A., Chatila, T.A., et al. 2014. Immunoglobulin E signal inhibition during allergen ingestion leads to reversal of established food allergy and induction of regulatory T cells.
Immunity 41:141-151.
5. Charbonnier, L.M., Wang, S., Georgiev, P., Sefik, E., and Chatila, T.A. 2015. Control of peripheral tolerance by regulatory T cell-intrinsic Notch signaling.
Nat Immunol 16:1162-1173.
6. Xia, M., Viera-Hutchins, L., Garcia-Lloret, M., Noval Rivas, M., Wise, P., McGhee, S.A., Chatila, Z.K., Daher, N., Sioutas, C., and Chatila, T.A. 2015. Vehicular exhaust particles promote allergic airway inflammation through an aryl hydrocarbon receptor-notch signaling cascade.
J Allergy Clin Immunol 136:441-453.
7. Charbonnier, L.M., Janssen, E., Chou, J., Ohsumi, T.K., Keles, S., Hsu, J.T., Massaad, M.J., Garcia-Lloret, M., Hanna-Wakim, R., Dbaibo, G., et al. 2015. Regulatory T-cell deficiency and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like disorder caused by loss-of-function mutations in LRBA.
J Allergy Clin Immunol 135:217-227.



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