Professor of Pediatrics
Karp Family Building, Room 10-214
1 Blackfan St.
Boston, MA 02115
A major focus of our studies has been the elucidation of genetic pathways regulating tolerance and to identify human diseases resulting from defects along those pathways. We have approached this issue from the perspective of Mendelian traits associated with allergic and immunological dysregulatory disorders. Our earlier studies have led to the identification of human mutations in the transcription factor Foxp3, later revealed to be critical for regulatory T (TR) cell differentiation and effector function. Foxp3 deficiency is associated with autoimmunity and allergic dysregulation, including food allergy, and our studies have focused on mechanisms by which disease manifestations evolve pursuant to TR cell deficiency. These studies have led to the delineation of the distinct functions of thymus derived (natural) versus de novo induced TR cells in tolerance maintenance in vivo, and the role of the microbial flora in promoting disease in Foxp3 deficiency. Current studies are examining the regulation by different genetic pathways of natural TR cell development and function, and the role of the microbiota in directing induced TR cell differentiation. More recently, we have identified the guanine nucleotide exchange factor DOCK8 to be the target of mutations in the autosomal recessive form of the hyper IgE syndrome (AR-HIES), a disease associated with severe eczema, food allergy, elevated IgE production, autoimmunity and an undue susceptibility to viral infections. Collaborative studies are now aimed at elucidating mechanisms by which DOCK8 deficiency disrupts tolerance and promotes different disease phenotypes.
A complementary approach has been to genetically map the function of signaling components along the IL-4/IL-13/IL-4R pathway, which plays a critical role in allergic diseases, in disrupting tolerance to allergens. Starting with our identification of asthma-associated polymorphisms in the IL-4 receptor alpha chain, we proceeded to derive the first murine model of an asthma associated human polymorphism and demonstrated that it directly promotes allergic airway inflammation in mice by a MAPK dependent mechanism. Other genetic mouse models mapped the contribution of IL-4R-coupled PI3-kinase and SHP-1 phosphatase pathways, establishing the function of these pathways in an in vivo context. Our current studies examine mechanisms by which IL-4R signaling compromises TR cell function, and epigenetic mechanisms by which different IL-4R pathways contribute to the chronicity of allergic diseases.
Lin W, Haribhai D, Relland LR, Truong N, Williams CB, Chatila TA. Regulatory T cell development in the absence of functional Foxp3. Nat. Immunol. 8: 359-68 (2007).
Tachdjian R, Mathias C, Al Khatib S, Bryce PJ, Blaeser F, Kim, HS, O’Connor BD, Rzymkiewicz D, Chen A, Holtzman MJ, Hershey GK, Garn H, Harb H, Renz H, Oettgen HC, Chatila TA. Pathogenicity of a Disease-Associated Human IL-4 Receptor Allele in Experimental Asthma. J. Exp. Med. 28; 206(10): 2191-204 (2009).
Engelhardt KR, McGhee S, Winkler S, Sassi A, Woellner C, Lopez-Herrera G, Chen A, Kim HS, Garcia-Lloret M, Schulze I, Ehl S, Thiel J, Pfeifer D, Veelken H, Niehues T, Siepermann K, Weinspach S, Reisli I, Keles S, Genel F, Kütükçüler N, Camcıoğlu Y, Somer A, Karakoc-Aydiner E, Barlan I, Gennery A, Metin A, Pietrogrande MC, Yeganeh M, Baz Z, Al-Tamemi S, Klein C, Puck JM, Holland SM, McCabe ERB, Grimbache B, Chatila TA. Large Deletions and Point Mutations Involving DOCK8 in the Autosomal Recessive Form of the Hyper-IgE Syndrome. J Allergy Clin Immunol. 124(6): 1289-302. (2009).
Haribhai D, Williams JB, Jia S, Nikerson D, Treslley-Schmitt E, Edwards B, Ziegelbauer J, Yassai M, Li S-H, Relland LR, Zheng Y, Simpson, PM, Gorski J, Salzman NH, Hessner MJ, Chatila TA*, Williams CB*. A Requisite role for induced regulatory T cells in Tolerance based on expanding antigen receptor diversity within regulatory responses. Immunity. 35(1): 109-22 (2011). (*Co-corresponding authors).
Noval Rivas M, Koh YT, Chen A, Nguyen A. Lee YH, Lawson G, Chatila TA. Critical Function of MyD88 in Immune Tolerance Breakdown in Murine Foxp3 Deficiency J. Clin. Invest. 122(5): 1933-47 (2012).
Last Update: 1/6/2014