title: Regulation of CD4⁺ and CD8⁺ effector responses by Sprouty-1.
abstract: TCR-induced NF-AT activation leads to the expression of both activating and inhibitory proteins. Previously, we had identified Egr-2 and Egr-3 as NF-AT-induced transcription factors which promote the inhibition of T cell activation. In this report we identify Sprouty1 as a downstream target of Egr-3. CD4⁺ T cells lacking Spry1 demonstrate enhanced proliferation and cytokine production. Likewise, Spry1(Flox/Flox) Lck Cre CD8⁺ T cells display increased cytolytic activity. Mechanistically, Spry1 acts at the level of PLC-γ promoting the inhibition of both Ca⁺⁺ induced NF-AT activation and MAP-kinase induced AP-1 activation while sparing NF-κB signaling. In vivo, mice in which Spry1 is selectively deleted in T cells demonstrate enhanced responses to a tumor vaccine and subsequently reject tumors more robustly than Wt mice. These findings suggest that targeting Spry1 might prove to be a novel means of enhancing tumor immunotherapy.
authors.affiliation: Department of Medicine, Division of Pulmonary and Critical Care, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Sam
authors.initials: S
authors.lastname: Collins
authors.forename: Adam
authors.initials: A
authors.lastname: Waickman
authors.forename: Albert
authors.initials: A
authors.lastname: Basson
authors.forename: Abraham
authors.initials: A
authors.lastname: Kupfer
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Licht
authors.forename: Maureen R
authors.initials: MR
authors.lastname: Horton
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Powell
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D045744:Cell Line, Tumor; D051776:Early Growth Response Protein 3 / Q000378:metabolism; D015870:Gene Expression; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D050778:NFATC Transcription Factors / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism; D051966:Phospholipase C gamma / Q000378:metabolism; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D008565:Membrane Proteins; D050778:NFATC Transcription Factors; D010750:Phosphoproteins; D011948:Receptors, Antigen, T-Cell; C425468:Spry1 protein, mouse; D018808:Transcription Factor AP-1; D051776:Early Growth Response Protein 3; D051966:Phospholipase C gamma