title: TGF-β1and contact mediated suppression by CD4+CD25+CD127-T regulatory cells of patients with self-limiting hepatitis E.
abstract: OBJECTIVE
  Literature on the role of Regulatory T cells (Tregs) in acute viral infections is limited. Having established that the Tregs in self-limiting hepatitis E infection are elevated and functional, this study has focused on characterizing the specificity, phenotypes and identifying the molecules or factors responsible for enhancement of Treg cells and abrogation of Treg-mediated suppression in hepatitis E.
  
  
  METHODS
  HEV rORF2p specific (a) Treg frequency, subset analysis and expression of surface and intracellular markers on Tregs and CFSE based functional analysis by flow cytometry (b) key cytokines quantification by multiplex (c) suppressive functional assay in the presence of anti-TGF-β1or anti-IL-10 or both antibodies or Transwell insert or in combination were performed on samples from 58 acute patients (AVH-E), 45 recovered individuals from hepatitis E and 55 controls.
  
  
  RESULTS
  In AVH-E, the increased frequencies of Tregs and Teff cells were HEV rORF2p specific and Treg cells were of effector memory phenotype. Higher expressions of HEV rORF2p stimulated CTLA-4, GITR, PD1L, CD103, CD39, TLR2 and TGF-β1molecules on Tregs of AVH-E were observed. Tregs produced TGF-β1and inhibited the secretion of IFN-γ. Transwell insert and cytokines blocking assays indicated Tregs mediated suppression in AVH-E patients is majorly TGF-β1mediated and partly cell-cell contact mediated.
  
  
  CONCLUSIONS
  Overall, we have identified beneficial involvement of HEV specific, functional Tregs and TGF-β1as the regulatory molecule responsible for enhancement of Tregs in self-limiting HEV infection. Therefore, use of TGF-β1as a possible supplement for boosting Treg response in recovery from severe hepatitis E needs evaluation.
authors.affiliation: Hepatitis Group, National Institute of Virology, Pune, India.
authors.forename: Sanjay B
authors.initials: SB
authors.lastname: Rathod
authors.affiliation: Hepatitis Group, National Institute of Virology, Pune, India. Electronic address: anuradhastripathy@hotmail.com.
authors.forename: Anuradha S
authors.initials: AS
authors.lastname: Tripathy
mesh_terms: D015704:CD4 Antigens / Q000378:metabolism; D049109:Cell Proliferation; D002469:Cell Separation; D002478:Cells, Cultured; D018450:Disease Progression; D005434:Flow Cytometry; D022001:Focal Adhesions; D016751:Hepatitis E / Q000276:immunology*; D016752:Hepatitis E virus / Q000502:physiology*; D006801:Humans; D007156:Immunologic Memory; D007165:Immunosuppression Therapy; D016753:Interleukin-10 / Q000276:immunology; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D053699:Interleukin-7 Receptor alpha Subunit / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000378:metabolism*; D014764:Viral Proteins / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; D053645:Interleukin-2 Receptor alpha Subunit; D053699:Interleukin-7 Receptor alpha Subunit; C400971:ORF2 protein, Hepatitis E virus; D053773:Transforming Growth Factor beta1; D014764:Viral Proteins; D016753:Interleukin-10
keywords: Hepatitis E; IL-10; TGF-β(1); Transwell assay; Treg