Phosphatase PTPN22 Regulates Dendritic Cell Homeostasis and cDC2 Dependent T Cell Responses
Year: 2020
Type: article
Abstract: Dendritic cells (DCs) are specialized antigen presenting cells that instruct T cell responses through sensing environmental and inflammatory danger signals. Maintaining the homeostasis of the multiple functionally distinct conventional dendritic cells (cDC) subsets that exist in vivo is crucial for regulating immune responses, with changes in numbers sufficient to break immune tolerance. Using Ptpn22-/- mice we demonstrate that the phosphatase PTPN22 is a highly selective, negative regulator of cDC2 homeostasis, preventing excessive population expansion from as early as 3 weeks of age. Mechanistically, PTPN22 mediates cDC2 homeostasis in a cell intrinsic manner by restricting cDC2 proliferation. A single nucleotide polymorphism, PTPN22R620W, is one of the strongest genetic risk factors for multiple autoantibody associated human autoimmune diseases. We demonstrate that cDC2 are also expanded in mice carrying the orthologous PTPN22619W mutation. As a consequence, cDC2 dependent CD4+ T cell proliferation and T follicular helper cell responses are increased. Collectively, our data demonstrate that PTPN22 controls cDC2 homeostasis, which in turn ensures appropriate cDC2-dependent T cell responses under antigenic challenge. Our findings provide a link between perturbations in DC development and susceptibility to a broad spectrum of PTPN22R620W associated human autoimmune diseases.
Source: Frontiers in Immunology
Institutions: King's College London, University of Washington, Seattle Children's Research Institute, Friedrich-Alexander-Universität Erlangen-Nürnberg, Centre for Immunity, Infection and Evolution, University of Edinburgh, Centre National de la Recherche Scientifique, Inserm, Université Paris Cité, Centre de Recherche sur l'Inflammation
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,950
Funders: Wellcome Trust, Cancer Research UK, National Institute for Health and Care Research, King's College London, Deutsche Forschungsgemeinschaft, Agence Nationale de la Recherche, Worldwide Cancer Research, Versus Arthritis, National Institutes of Health, Biotechnology and Biological Sciences Research Council, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: G1037940132, G219623343, G2608481872, G286061565, Mechanisms and consequences of T cell antigen receptor signalling for normal immune homeostasis and the development of autoimmune disease, G3391371681, Antigen presentation by MHCII in cross-presenting dendritic cells., Defining the functional impact of T1D genes in mouse and man: a unified strategy, G4617376168, G4653702389, G5789791028, Development and function of inflammatory dendritic cells, G6267375426, G7317887839, An integrated strategy to define the functional and synergistic impact of T1D causal variants
OpenAlex ID: W3009308211