title: Role of regulator of G protein signaling 16 in inflammation-induced T lymphocyte migration and activation.
abstract: Chemokine-induced T lymphocyte recruitment to the lung is critical for allergic inflammation, but chemokine signaling pathways are incompletely understood. Regulator of G protein signaling (RGS)16, a GTPase accelerator (GTPase-activating protein) for Galpha subunits, attenuates signaling by chemokine receptors in T lymphocytes, suggesting a role in the regulation of lymphocyte trafficking. To explore the role of RGS16 in T lymphocyte-dependent immune responses in a whole-organism model, we generated transgenic (Tg) mice expressing RGS16 in CD4(+) and CD8(+) cells. rgs16 Tg T lymphocytes migrated to CC chemokine ligand 21 or CC chemokine ligand 12 injection sites in the peritoneum, but not to CXC chemokine ligand 12. In a Th2-dependent model of allergic pulmonary inflammation, CD4(+) lymphocytes bearing CCR3, CCR5, and CXCR4 trafficked in reduced numbers to the lung after acute inhalation challenge with allergen (OVA). In contrast, spleens of sensitized and challenged Tg mice contained increased numbers of CD4(+)CCR3(+) cells producing more Th2-type cytokines (IL-4, IL-5, and IL-13), which were associated with increased airway hyperreactivity. Migration of Tg lymphocytes to the lung parenchyma after adoptive transfer was significantly reduced compared with wild-type lymphocytes. Naive lymphocytes displayed normal CCR3 and CXCR4 expression and cytokine responses, and compartmentation in secondary lymphoid organs was normal without allergen challenge. These results suggest that RGS16 may regulate T lymphocyte activation in response to inflammatory stimuli and migration induced by CXCR4, CCR3, and CCR5, but not CCR2 or CCR7.
authors.affiliation: Molecular Signal Transduction Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD 20852, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Lippert
authors.forename: David L
authors.initials: DL
authors.lastname: Yowe
authors.forename: Jose-Angel
authors.initials: JA
authors.lastname: Gonzalo
authors.forename: J Paul
authors.initials: JP
authors.lastname: Justice
authors.forename: Jeremy M
authors.initials: JM
authors.lastname: Webster
authors.forename: Eric R
authors.initials: ER
authors.lastname: Fedyk
authors.forename: Martin
authors.initials: M
authors.lastname: Hodge
authors.forename: Cheryl
authors.initials: C
authors.lastname: Miller
authors.forename: Jose-Carlos
authors.initials: JC
authors.lastname: Gutierrez-Ramos
authors.forename: Francisco
authors.initials: F
authors.lastname: Borrego
authors.forename: Andrea
authors.initials: A
authors.lastname: Keane-Myers
authors.forename: Kirk M
authors.initials: KM
authors.lastname: Druey
mesh_terms: D000208:Acute Disease; D019264:Adoptive Transfer; D000485:Allergens / Q000008:administration & dosage; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000276:immunology*; D003433:Crosses, Genetic; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D005260:Female; D006706:Homeostasis / Q000235:genetics / Q000276:immunology; D006801:Humans; D007114:Immunization; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008168:Lung / Q000276:immunology / Q000473:pathology*; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008221:Lymphoid Tissue / Q000254:growth & development / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D010047:Ovalbumin / Q000008:administration & dosage / Q000276:immunology; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D020710:RGS Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology* / Q000637:transplantation; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology
chemical_list: D000485:Allergens; D016207:Cytokines; D011506:Proteins; D020710:RGS Proteins; C107413:RGS16 protein; D019707:Receptors, Chemokine; D010047:Ovalbumin