title: CD4+ CD25(high) Foxp3+ regulatory T cells downregulate human Vdelta2+ T-lymphocyte function triggered by anti-CD3 or phosphoantigen.
abstract: Vdelta2+ T cells, the major circulating T-cell receptor-gammadelta-positive (TCR-gammadelta+) T-cell subset in healthy adults, are involved in immunity against many microbial pathogens including Mycobacterium tuberculosis. Vdelta2+ T cells recognize small phosphorylated metabolites (phosphoantigens), expand in response to whole M. tuberculosis bacilli, and complement the protective functions of CD4+ T cells. CD4+ CD25(high) Foxp3+ T cells (Tregs) comprise 5-10% of circulating T cells and are increased in patients with active tuberculosis (TB). We investigated whether, in addition to their known role in suppressing TCR-alphabeta+ lymphocytes, Tregs suppress Vdelta2+ T-cell function. We found that depletion of Tregs from peripheral blood mononuclear cells increased Vdelta2+ T-cell expansion in response to M. tuberculosis (H37Ra) in tuberculin-skin-test-positive donors. We developed a suppression assay with fluorescence-activated cell sorting-purified Tregs and Vdelta2+ T cells by coincubating the two cell types at a 1 : 1 ratio. The Tregs partially suppressed interferon-gamma secretion by Vdelta2+ T cells in response to anti-CD3 monoclonal antibody plus interleukin-2 (IL-2). In addition, Tregs downregulated the Vdelta2+ T-cell interferon-gamma responses induced by phosphoantigen (BrHPP) and IL-2. Under the latter conditions there was no TCR stimulus for Tregs and therefore IL-2 probably triggered suppressor activity. Addition of purified protein derivative (PPD) increased the suppression of Vdelta2+ T cells, suggesting that PPD activated antigen-specific Tregs. Our study provides evidence that Tregs suppress both anti-CD3 and antigen-driven Vdelta2+ T-cell activation. Antigen-specific Tregs may therefore contribute to the Vdelta2+ T-cell functional deficiencies observed in TB.
authors.affiliation: Department of Medicine, Division of Infectious Diseases, MetroHealth Medical Center, MetroHealth Drive, Cleveland, OH 44109, USA. csmahan@gmail.com
authors.forename: C Scott
authors.initials: CS
authors.lastname: Mahan
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Thomas
authors.forename: W Henry
authors.initials: WH
authors.lastname: Boom
authors.forename: Roxana E
authors.initials: RE
authors.lastname: Rojas
mesh_terms: D000293:Adolescent; D000328:Adult; D017252:CD3 Complex / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D015536:Down-Regulation / Q000276:immunology; D051858:Forkhead Transcription Factors / Q000032:analysis; D006801:Humans; D007108:Immune Tolerance; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D008213:Lymphocyte Activation / Q000276:immunology; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000276:immunology; D010750:Phosphoproteins / Q000276:immunology*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014373:Tuberculin / Q000276:immunology; D014374:Tuberculin Test; D014376:Tuberculosis / Q000276:immunology*; D055815:Young Adult
chemical_list: D017252:CD3 Complex; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D010750:Phosphoproteins; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014373:Tuberculin