Subject(s)
Diabetes Mellitus, Type 1 , Feeding and Eating Disorders , Humans , Diabetes Mellitus, Type 1/psychology , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/therapy , Prospective Studies , Feeding and Eating Disorders/therapy , Feeding and Eating Disorders/psychology , Female , Male , Adult , Proof of Concept Study , Mental Health , Cohort StudiesABSTRACT
Autoimmune diseases such as multiple sclerosis (MS) are thought to develop due to a dysregulation in the normal T(H)1-T(H)17/T(H)2 immune system balance, where pro-inflammatory responses with a T(H)1/T(H)17 prevalence develop. Some therapeutic treatments in MS promote a shift toward a TH2-prevalent environment and this has been shown to be protective. However, not all patients respond to current immunomodulatory treatments in MS so that new immunomodulatory drugs that can promote a shift of the immune system into an anti-inflammatory T(H)2 status are needed. IL-25 is a cytokine of the IL-17 family with powerful anti-inflammatory properties. This study demonstrates that IL-25 exerts neuroprotective functions by reducing T cell-mediated killing of human fetal neurons. The mechanism of action of this IL-25-mediated neuroprotective effect appears to be linked to reduction in the expression of the adhesion molecule LFA-1, which is relevant in stabilizing the immune synapse during cytotoxicity.
Subject(s)
Gene Expression Regulation/drug effects , Interleukin-17/pharmacology , Lymphocyte Function-Associated Antigen-1/metabolism , Neuroprotective Agents/pharmacology , T-Lymphocytes/physiology , Antibodies/pharmacology , CD28 Antigens/immunology , CD3 Complex/immunology , Cell Proliferation/drug effects , Cells, Cultured , Coculture Techniques , Culture Media, Conditioned/pharmacology , Cytokines/metabolism , Fetus/cytology , Flow Cytometry , Gene Expression Regulation/immunology , Humans , Interleukin-7/metabolism , Microtubule-Associated Proteins/metabolism , Neurons , Ovalbumin/pharmacology , Statistics, Nonparametric , Time FactorsABSTRACT
MS lesions are characterized by destruction of myelin and significant neuronal and axonal loss. Preliminary studies with the use of T(regs) in the mouse model of MS have been extremely encouraging. However, recent studies with human cells have shown the presence of different subpopulations of T cells within the CD4(+)CD25(+)Foxp3(+) T cell phenotype, some of which do not have regulatory functions. These findings suggest a potential difference between mouse and human in the regulatory phenotype. Here, we show that human activated CD4(+)CD25(+)Foxp3(+) T cells are neurotoxic in vitro. These cells expressed high levels of the cytotoxic molecule GrB and had no suppressive effect. On the contrary, they produced IFN-γ and low IL-17, suggesting a shift toward a T(H)1 phenotype. Thus, our data confirm the presence of a nonregulatory cytotoxic subpopulation within the human CD4(+)CD25(+)Foxp3(+) T cells and suggest further studies on the human regulatory phenotype prior to any potential therapeutic application.
