title: Notch Ligand Delta-like 4 Promotes Regulatory T Cell Identity in Pulmonary Viral Infection.
abstract: Regulatory T (Treg) cells establish tolerance, prevent inflammation at mucosal surfaces, and regulate immunopathology during infectious responses. Recent studies have shown that Delta-like ligand 4 (Dll4) was upregulated on APC after respiratory syncytial virus (RSV) infection, and its inhibition leads to exaggerated immunopathology. In the present study, we outline the role of Dll4 in Tregcell differentiation, stability, and function in RSV infection. We found that Dll4 was expressed on CD11b+pulmonary dendritic cells in the lung and draining lymph nodes in wild-type BALB/c mice after RSV infection. Dll4 neutralization exacerbated RSV-induced disease pathology, mucus production, group 2 innate lymphoid cell infiltration, IL-5 and IL-13 production, as well as IL-17A+CD4 T cells. Dll4 inhibition decreased the abundance of CD62LhiCD44loFoxp3+central Tregcells in draining lymph nodes. The RSV-induced disease was accompanied by an increase in Th17-like effector phenotype in Foxp3+Tregcells and a decrease in granzyme B expression after Dll4 blockade. Finally, Dll4-exposed induced Tregcells maintained the CD62LhiCD44locentral Tregcell phenotype, had increased Foxp3 expression, became more suppressive, and were resistant to Th17 skewing in vitro. These results suggest that Dll4 activation during differentiation sustained Tregcell phenotype and function to control RSV infection.
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Hung-An
authors.initials: HA
authors.lastname: Ting
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Matthew A
authors.identifier: 0000-0003-3338-0655
authors.initials: MA
authors.lastname: Schaller
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Denise E
authors.initials: DE
authors.lastname: de Almeida Nagata
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Andrew J
authors.identifier: 0000-0002-8009-4953
authors.initials: AJ
authors.lastname: Rasky
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109.|Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109; and.|Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109.
authors.forename: Ivan P
authors.identifier: 0000-0003-1312-6748
authors.initials: IP
authors.lastname: Maillard
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI 48109; nlukacs@med.umich.edu.
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Lukacs
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002135:Calcium-Binding Proteins; D002454:Cell Differentiation; D003713:Dendritic Cells / Q000276:immunology / Q000821:virology; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D053804:Granzymes / Q000235:genetics; D018793:Interleukin-13 / Q000276:immunology; D015848:Interleukin-5 / Q000276:immunology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D019041:L-Selectin / Q000235:genetics / Q000276:immunology; D008168:Lung / Q000166:cytology / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology* / Q000503:physiopathology / Q000821:virology; D012136:Respiratory Syncytial Viruses / Q000276:immunology / Q000302:isolation & purification; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000502:physiology*; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018793:Interleukin-13; D015848:Interleukin-5; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D019041:L-Selectin; D053804:Granzymes; C509214:Gzmb protein, mouse