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-κB 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.