The pathogen recognition receptor NOD2 regulates human FOXP3+ T cell survival

• Published in: The Journal of immunology (1950) 2010-06, Vol.184 (12), p.7247-7256
• Main Authors: Rahman, Meher K, Midtling, Emilie H, Svingen, Phyllis A, Xiong, Yuning, Bell, Michael P, Tung, Jeanne, Smyrk, Tom, Egan, Larry J, Faubion, Jr, William A
• Format: Article
• Language: English
• Subjects: Apoptosis - genetics; Apoptosis - immunology; Blotting, Western; Cell Separation; Cell Survival; Crohn Disease - genetics; Crohn Disease - immunology; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Forkhead Transcription Factors - immunology; Forkhead Transcription Factors - metabolism; Genotype; Humans; Immunohistochemistry; Intestinal Mucosa - immunology; Intestinal Mucosa - metabolism; Male; Middle Aged; Nod2 Signaling Adaptor Protein - genetics; Nod2 Signaling Adaptor Protein - immunology; Nod2 Signaling Adaptor Protein - metabolism; Polymorphism, Single Nucleotide; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Transfection
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.0901479

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.