ABSTRACT
Sphingosine-1 phosphate receptor 1 (S1P1) is critical for the egress of T and B cells out of lymphoid organs. Although S1P1 agonist fingolimod is currently used for the treatment of multiple sclerosis (MS) little is known how S1P1 signaling regulates Th17 and Treg cell homeostasis. To study the impact of S1P1 signaling on Th17 and Treg cell biology, we specifically deleted S1P1 in Th17 and Treg cells using IL-17A Cre and Foxp3 Cre mice, respectively. Deletion of S1P1 in Th17 cells conferred resistance to experimental autoimmune encephalomyelitis (EAE). On the other hand, permanent deletion of S1P1 in Treg cells resulted in autoimmunity and acute deletion rendered mice more susceptible to EAE. Importantly, our study revealed that S1P1 not only regulated the egress of Treg cells out of lymphoid organs and subsequent non-lymphoid tissue distribution but also their phenotypic diversity. Most of the Treg cells found in S1P1-deficient mice as well as MS patients on fingolimod therapy had an activated phenotype and were more prone to apoptosis, thus converted to effector Treg. Our results provide novel insight into the functions of S1P1 and potential impact of long term fingolimod use on Th17 and Treg cell biology and general health in MS patients.
Subject(s)
Gene Deletion , Receptors, Lysosphingolipid/genetics , T-Lymphocytes, Regulatory/immunology , Th17 Cells/immunology , Animals , Autoimmunity , Case-Control Studies , Disease Susceptibility , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Fingolimod Hydrochloride/pharmacology , Fingolimod Hydrochloride/therapeutic use , Humans , Inflammation/pathology , Lymphadenopathy/pathology , Lymphoid Tissue/pathology , Mice , Mice, Inbred C57BL , Multiple Sclerosis/drug therapy , Multiple Sclerosis/immunology , Multiple Sclerosis/pathology , Organ Specificity , Phenotype , Receptors, Lysosphingolipid/metabolism , Transcription, GeneticABSTRACT
Retinoic acid receptor-related orphan receptor-γt-positive (RORγt(+)) innate lymphoid cells (ILCs) produce interleukin (IL)-22 and IL-17, which are critical for protective immunity against enteric pathogens. The molecular mechanism underlying the development and survival of RORγt(+) ILCs is not thoroughly understood. Here, we show that Dedicator of cytokinesis 8 (DOCK8), a scaffolding protein involved in cytoskeletal rearrangement and cell migration, is essential for the protective immunity against Citrobacter rodentium. A comparative RNA sequencing-based analysis reveals an impaired induction of antimicrobial peptides in the colon of DOCK8-deficient mice, which correlates with high susceptibility to infection and a very low number of IL-22-producing RORγt(+) ILCs in their GI tract. Furthermore, DOCK8-deficient RORγt(+) ILCs are less responsive to IL-7 mediated signalling, more prone to apoptosis and produce less IL-22 due to a defect in IL-23-mediated STAT3 phosphorylation. Our studies reveal an unsuspected role of DOCK8 for the function, generation and survival of RORγt(+) ILCs.
