PMID- 32194571 OWN - NLM STAT- MEDLINE DCOM- 20210323 LR - 20230315 IS - 1664-3224 (Electronic) IS - 1664-3224 (Linking) VI - 11 DP - 2020 TI - Phosphatase PTPN22 Regulates Dendritic Cell Homeostasis and cDC2 Dependent T Cell Responses. PG - 376 LID - 10.3389/fimmu.2020.00376 [doi] LID - 376 AB - 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, PTPN22(R620W), 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 PTPN22(619W) 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 PTPN22(R620W) associated human autoimmune diseases. CI - Copyright (c) 2020 Purvis, Clarke, Montgomery, Colas, Bibby, Cornish, Dai, Dudziak, Rawlings, Zamoyska, Guermonprez and Cope. FAU - Purvis, Harriet A AU - Purvis HA AD - Faculty of Life Sciences and Medicine, Centre for Inflammation Biology and Cancer Immunology, King's College London, London, United Kingdom. FAU - Clarke, Fiona AU - Clarke F AD - Faculty of Life Sciences and Medicine, Centre for Inflammation Biology and Cancer Immunology, King's College London, London, United Kingdom. FAU - Montgomery, Anna B AU - Montgomery AB AD - Faculty of Life Sciences and Medicine, Centre for Inflammation Biology and Cancer Immunology, King's College London, London, United Kingdom. FAU - Colas, Chloe AU - Colas C AD - Faculty of Life Sciences and Medicine, Centre for Inflammation Biology and Cancer Immunology, King's College London, London, United Kingdom. FAU - Bibby, Jack A AU - Bibby JA AD - Faculty of Life Sciences and Medicine, Centre for Inflammation Biology and Cancer Immunology, King's College London, London, United Kingdom. FAU - Cornish, Georgina H AU - Cornish GH AD - Faculty of Life Sciences and Medicine, Centre for Inflammation Biology and Cancer Immunology, King's College London, London, United Kingdom. FAU - Dai, Xuezhi AU - Dai X AD - Seattle Children's Research Institute, Seattle, WA, United States. AD - Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, United States. AD - Department of Immunology, University of Washington School of Medicine, Seattle, WA, United States. FAU - Dudziak, Diana AU - Dudziak D AD - Laboratory of Dendritic Cell Biology, Department of Dermatology, Friedrich-Alexander University of Erlangen, Erlangen, Germany. FAU - Rawlings, David J AU - Rawlings DJ AD - Seattle Children's Research Institute, Seattle, WA, United States. AD - Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, United States. AD - Department of Immunology, University of Washington School of Medicine, Seattle, WA, United States. FAU - Zamoyska, Rose AU - Zamoyska R AD - Centre for Immunity, Infection and Evolution, Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom. FAU - Guermonprez, Pierre AU - Guermonprez P AD - Faculty of Life Sciences and Medicine, Centre for Inflammation Biology and Cancer Immunology, King's College London, London, United Kingdom. AD - Centre for Inflammation Research, CNRS ERL8252, INSERM1149, Universite de Paris, Paris, France. FAU - Cope, Andrew P AU - Cope AP AD - Faculty of Life Sciences and Medicine, Centre for Inflammation Biology and Cancer Immunology, King's College London, London, United Kingdom. LA - eng GR - 096669AIA/WT_/Wellcome Trust/United Kingdom GR - DH_/Department of Health/United Kingdom GR - DP3 DK111802/DK/NIDDK NIH HHS/United States GR - 20525/VAC_/Versus Arthritis/United Kingdom GR - C57672/A22369/CRUK_/Cancer Research UK/United Kingdom GR - 20218/VAC_/Versus Arthritis/United Kingdom GR - 205014/Z/16/Z/WT_/Wellcome Trust/United Kingdom GR - DP3 DK097672/DK/NIDDK NIH HHS/United States GR - WT_/Wellcome Trust/United Kingdom GR - BB/M029735/1/BB_/Biotechnology and Biological Sciences Research Council/United Kingdom PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20200304 PL - Switzerland TA - Front Immunol JT - Frontiers in immunology JID - 101560960 RN - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 22) RN - EC 3.1.3.48 (Ptpn22 protein, mouse) SB - IM MH - Animals MH - Autoimmunity/*immunology MH - Dendritic Cells/*immunology MH - Homeostasis/immunology MH - Immune Tolerance/immunology MH - Lymphocyte Activation/*immunology MH - Mice MH - Mice, Transgenic MH - Polymorphism, Single Nucleotide MH - Protein Tyrosine Phosphatase, Non-Receptor Type 22/genetics/*immunology MH - T-Lymphocytes, Helper-Inducer/*immunology PMC - PMC7065600 OTO - NOTNLM OT - PTPN22 OT - T follicular helper cell OT - autoimmunity OT - cDC2 OT - dendritic cell OT - homeostasis OT - polymorphism OT - proliferation EDAT- 2020/03/21 06:00 MHDA- 2021/03/24 06:00 PMCR- 2020/01/01 CRDT- 2020/03/21 06:00 PHST- 2019/09/27 00:00 [received] PHST- 2020/02/17 00:00 [accepted] PHST- 2020/03/21 06:00 [entrez] PHST- 2020/03/21 06:00 [pubmed] PHST- 2021/03/24 06:00 [medline] PHST- 2020/01/01 00:00 [pmc-release] AID - 10.3389/fimmu.2020.00376 [doi] PST - epublish SO - Front Immunol. 2020 Mar 4;11:376. doi: 10.3389/fimmu.2020.00376. eCollection 2020.