title: Mycobacteria-responsive sonic hedgehog signaling mediates programmed death-ligand 1- and prostaglandin E2-induced regulatory T cell expansion.
abstract: CD4(+)CD25(+)FoxP3(+) regulatory T cells (Tregs) are exploited by mycobacteria to subvert the protective host immune responses. The Treg expansion in the periphery requires signaling by professional antigen presenting cells and in particularly dendritic cells (DC). However, precise molecular mechanisms by which mycobacteria instruct Treg expansion via DCs are not established. Here we demonstrate that mycobacteria-responsive sonic hedgehog (SHH) signaling in human DCs leads to programmed death ligand-1 (PD-L1) expression and cyclooxygenase (COX)-2-catalyzed prostaglandin E2 (PGE2) that orchestrate mycobacterial infection-induced expansion of Tregs. While SHH-responsive transcription factor GLI1 directly arbitrated COX-2 transcription, specific microRNAs, miR-324-5p and miR-338-5p, which target PD-L1 were downregulated by SHH signaling. Further, counter-regulatory roles of SHH and NOTCH1 signaling during mycobacterial-infection of human DCs was also evident. Together, our results establish that Mycobacterium directs a fine-balance of host signaling pathways and molecular regulators in human DCs to expand Tregs that favour immune evasion of the pathogen.
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Sahana
authors.initials: S
authors.lastname: Holla
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1138, Paris, France.|Centre de Recherche des Cordeliers, Equipe-Immunopathology and therapeutic immunointervention, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S 1138, Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Stephen-Victor
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Praveen
authors.initials: P
authors.lastname: Prakhar
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1138, Paris, France.|Centre de Recherche des Cordeliers, Equipe-Immunopathology and therapeutic immunointervention, Paris, France.
authors.forename: Meenu
authors.initials: M
authors.lastname: Sharma
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1138, Paris, France.|Centre de Recherche des Cordeliers, Equipe-Immunopathology and therapeutic immunointervention, Paris, France.|Université de Technologie de Compiègne, Compiègne, France.
authors.forename: Chaitrali
authors.initials: C
authors.lastname: Saha
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Vibha
authors.initials: V
authors.lastname: Udupa
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1138, Paris, France.|Centre de Recherche des Cordeliers, Equipe-Immunopathology and therapeutic immunointervention, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S 1138, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, UMR S 1138, Paris, France.
authors.forename: Srinivas V
authors.initials: SV
authors.lastname: Kaveri
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité 1138, Paris, France.|Centre de Recherche des Cordeliers, Equipe-Immunopathology and therapeutic immunointervention, Paris, France.|Sorbonne Universités, UPMC Univ Paris 06, UMR S 1138, Paris, France.|Université Paris Descartes, Sorbonne Paris Cité, UMR S 1138, Paris, France.
authors.forename: Jagadeesh
authors.initials: J
authors.lastname: Bayry
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore, Karnataka, India.
authors.forename: Kithiganahalli Narayanaswamy
authors.initials: KN
authors.lastname: Balaji
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D009161:Mycobacterium / Q000276:immunology*; D009163:Mycobacterium bovis / Q000276:immunology; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: D060890:B7-H1 Antigen; D051546:Cyclooxygenase 2; D015232:Dinoprostone; D053823:Hedgehog Proteins; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D051880:Receptors, Notch; D058570:TOR Serine-Threonine Kinases