title: The pathogen recognition receptor NOD2 regulates human FOXP3+ T cell survival.
abstract: The expression of pathogen recognition receptors in human FOXP3+ T regulatory cells is established, yet the function of these receptors is currently obscure. In the process of studying the function of both peripheral and lamina propria FOXP3+ lymphocytes in patients with the human inflammatory bowel disease Crohn's disease, we observed a clear deficiency in the quantity of FOXP3+ lymphocytes in patients with disease-associated polymorphisms in the pathogen recognition receptor gene NOD2. Subsequently, we determined that the NOD2 ligand, muramyl dipeptide (MDP), activates NF-kappaB in primary human FOXP3+ T cells. This activation is functionally relevant, as MDP-stimulated human FOXP3+ T cells are protected from death receptor Fas-mediated apoptosis. Importantly, apoptosis protection was not evident in MDP-stimulated FOXP3+ T cells isolated from a patient with the disease-associated polymorphism. Thus, we propose that one function of pathogen recognition receptors in human T regulatory cells is the protection against death receptor-mediated apoptosis in a Fas ligand-rich environment, such as that of the inflamed intestinal subepithelial space.
authors.affiliation: Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Meher K
authors.initials: MK
authors.lastname: Rahman
authors.forename: Emilie H
authors.initials: EH
authors.lastname: Midtling
authors.forename: Phyllis A
authors.initials: PA
authors.lastname: Svingen
authors.forename: Yuning
authors.initials: Y
authors.lastname: Xiong
authors.forename: Michael P
authors.initials: MP
authors.lastname: Bell
authors.forename: Jeanne
authors.initials: J
authors.lastname: Tung
authors.forename: Tom
authors.initials: T
authors.lastname: Smyrk
authors.forename: Larry J
authors.initials: LJ
authors.lastname: Egan
authors.forename: William A
authors.initials: WA
authors.lastname: Faubion
mesh_terms: D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D015153:Blotting, Western; D002469:Cell Separation; D002470:Cell Survival; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology* / Q000378:metabolism; D005838:Genotype; D006801:Humans; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D053473:Nod2 Signaling Adaptor Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D014162:Transfection
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D034741:RNA, Small Interfering