The pathogen recognition receptor NOD2 regulates human FOXP3+ T cell survival.
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.
Rahman
Meher K
MK
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Midtling
Emilie H
EH
Svingen
Phyllis A
PA
Xiong
Yuning
Y
Bell
Michael P
MP
Tung
Jeanne
J
Smyrk
Tom
T
Egan
Larry J
LJ
Faubion
William A
WA
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
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C429018:NOD2 protein, human; D053473:Nod2 Signaling Adaptor Protein; D034741:RNA, Small Interfering