title: Murine IL-17+ Vγ4 T lymphocytes accumulate in the lungs and play a protective role during severe sepsis.
abstract: BACKGROUND
  Lung inflammation is a major consequence of the systemic inflammatory response caused by severe sepsis. Increased migration of γδ T lymphocytes into the lungs has been previously demonstrated during experimental sepsis; however, the involvement of the γδ T cell subtype Vγ4 has not been previously described.
  
  
  METHODS
  Severe sepsis was induced by cecal ligation and puncture (CLP; 9 punctures, 21G needle) in male C57BL/6 mice. γδ and Vγ4 T lymphocyte depletion was performed by 3A10 and UC3-10A6 mAb i.p. administration, respectively. Lung infiltrating T lymphocytes, IL-17 production and mortality rate were evaluated.
  
  
  RESULTS
  Severe sepsis induced by CLP in C57BL/6 mice led to an intense lung inflammatory response, marked by the accumulation of γδ T lymphocytes (comprising the Vγ4 subtype). γδ T lymphocytes present in the lungs of CLP mice were likely to be originated from peripheral lymphoid organs and migrated towards CCL2, CCL3 and CCL5, which were highly produced in response to CLP-induced sepsis. Increased expression of CD25 by Vγ4 T lymphocytes was observed in spleen earlier than that by αβ T cells, suggesting the early activation of Vγ4 T cells. The Vγ4 T lymphocyte subset predominated among the IL-17(+) cell populations present in the lungs of CLP mice (unlike Vγ1 and αβ T lymphocytes) and was strongly biased toward IL-17 rather than toward IFN-γ production. Accordingly, the in vivo administration of anti-Vγ4 mAb abrogated CLP-induced IL-17 production in mouse lungs. Furthermore, anti-Vγ4 mAb treatment accelerated mortality rate in severe septic mice, demonstrating that Vγ4 T lymphocyte play a beneficial role in host defense.
  
  
  CONCLUSIONS
  Overall, our findings provide evidence that early-activated Vγ4 T lymphocytes are the main responsible cells for IL-17 production in inflamed lungs during the course of sepsis and delay mortality of septic mice.
authors.affiliation: Laboratório de Farmacologia Aplicada, Departamento de Farmacologia, Farmanguinhos, Fundação Oswaldo Cruz, Rua Sizenando Nabuco 100, Manguinhos, Rio de Janeiro, RJ, CEP 21041-250, Brazil. mfcosta@cdts.fiocruz.br.|Centro de Desenvolvimento Tecnológico em Saúde, Instituto Nacional de Ciência e Tecnologia de Inovação em Doenças Negligenciadas (INCT-IDN), Fundação Oswaldo Cruz, Rio de Janeiro, Brazil. mfcosta@cdts.fiocruz.br.
authors.forename: Maria Fernanda de Souza
authors.initials: MF
authors.lastname: Costa
authors.affiliation: Laboratório de Farmacologia Aplicada, Departamento de Farmacologia, Farmanguinhos, Fundação Oswaldo Cruz, Rua Sizenando Nabuco 100, Manguinhos, Rio de Janeiro, RJ, CEP 21041-250, Brazil. catarinanegreiros@far.fiocruz.br.
authors.forename: Catarina Bastos Trigo
authors.initials: CB
authors.lastname: de Negreiros
authors.affiliation: Laboratório de Farmacologia Aplicada, Departamento de Farmacologia, Farmanguinhos, Fundação Oswaldo Cruz, Rua Sizenando Nabuco 100, Manguinhos, Rio de Janeiro, RJ, CEP 21041-250, Brazil. victo.bornstein@mssm.edu.|Mount Sinai School of Medicine, New York City, USA. victo.bornstein@mssm.edu.
authors.forename: Victor Ugarte
authors.initials: VU
authors.lastname: Bornstein
authors.affiliation: Laboratório de Toxinologia, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil. rhv4u@ioc.fiocruz.br.
authors.forename: Richard Hemmi
authors.initials: RH
authors.lastname: Valente
authors.affiliation: Laboratório de Imunologia, Faculdade de Medicina de Petrópolis, Petrópolis, Rio de Janeiro, Brazil. jomengel@fiocruz.br.|Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil. jomengel@fiocruz.br.
authors.forename: José
authors.initials: J
authors.lastname: Mengel
authors.affiliation: Laboratório de Farmacologia Aplicada, Departamento de Farmacologia, Farmanguinhos, Fundação Oswaldo Cruz, Rua Sizenando Nabuco 100, Manguinhos, Rio de Janeiro, RJ, CEP 21041-250, Brazil. gracahenriques@fiocruz.br.|Centro de Desenvolvimento Tecnológico em Saúde, Instituto Nacional de Ciência e Tecnologia de Inovação em Doenças Negligenciadas (INCT-IDN), Fundação Oswaldo Cruz, Rio de Janeiro, Brazil. gracahenriques@fiocruz.br.
authors.forename: Maria das Graças
authors.initials: Md
authors.lastname: Henriques
authors.affiliation: Laboratório de Inflamação, Estresse Oxidativo e Câncer, Centro de Ciências da Saúde, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil. cbenjamim@icb.ufrj.br.
authors.forename: Claudia Farias
authors.initials: CF
authors.lastname: Benjamim
authors.affiliation: Laboratório de Farmacologia Aplicada, Departamento de Farmacologia, Farmanguinhos, Fundação Oswaldo Cruz, Rua Sizenando Nabuco 100, Manguinhos, Rio de Janeiro, RJ, CEP 21041-250, Brazil. cpenido@cdts.fiocruz.br.|Centro de Desenvolvimento Tecnológico em Saúde, Instituto Nacional de Ciência e Tecnologia de Inovação em Doenças Negligenciadas (INCT-IDN), Fundação Oswaldo Cruz, Rio de Janeiro, Brazil. cpenido@cdts.fiocruz.br.
authors.forename: Carmen
authors.initials: C
authors.lastname: Penido
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D002432:Cecum / Q000187:drug effects / Q000473:pathology; D002465:Cell Movement / Q000187:drug effects; D018925:Chemokines / Q000378:metabolism; D020381:Interleukin-17 / Q000096:biosynthesis / Q000378:metabolism*; D008026:Ligation; D008168:Lung / Q000276:immunology* / Q000473:pathology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008810:Mice, Inbred C57BL; D020011:Protective Agents / Q000378:metabolism; D011677:Punctures; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D018805:Sepsis / Q000276:immunology* / Q000473:pathology*; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D016019:Survival Analysis; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D018925:Chemokines; D020381:Interleukin-17; D020011:Protective Agents; D016692:Receptors, Antigen, T-Cell, gamma-delta