title: Spi6 protects alloreactive CD4(+) but not CD8 (+) memory T cell from granzyme B attack by double-negative T regulatory cell.
abstract: Memory T (Tm) cells pose a major barrier to long-term transplant survival. Whether regulatory T cells (Tregs)can control them remains poorly defined. Previously,we established that double-negative (DN) Tregs suppress effector T (Teff) cells. Here, we demonstrate that DNTregs effectively suppress CD4+/CD8+Teff and CD8+Tm but not CD4+Tm cells, whereas the suppression on CD8+Tm is abrogated by perforin (PFN) deficiency in DNTregs. Consistently, in a BALB/c to B6-Rag1-/-skin transplantation, transfer of DN Tregs suppressed the rejection mediated by CD4þ/CD8+Teff and CD8+Tmcells (76.0±4.9, 87.5±5.0 and 63.0±4.7 days, respectively)but not CD4þTmcells (25.3±1.4 days). Both CD8þ effector memory T and central memory T compartments significantly reduced after DN Treg transfer. CD4+Tm highly expresses granzyme B (GzmB) inhibitor serine protease inhibitor-6 (Spi6). Spi6 deficiency renders CD4þTm susceptible to DN Treg suppression. In addition,transfer of WT DN Tregs, but not PFN-/-DN Tregs,inhibited the skin allograft rejection mediated by Spi6-/-CD4þTm(75.5±7.9 days). In conclusion, CD4+ and CD8+Tm cells differentially respond toDNTregs’ suppression.The GzmB resistance conferred by Spi6 in CD4þTm cells might hint at the physiological significance of Tmpersistence
authors.forename: Y
authors.initials: Y
authors.lastname: Su
authors.forename: A M
authors.initials: AM
authors.lastname: Jevnikar
authors.forename: X
authors.initials: X
authors.lastname: Huang
authors.forename: D
authors.initials: D
authors.lastname: Lian
authors.forename: Z -X
authors.initials: Z-
authors.lastname: Zhang
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D053222:Fas Ligand Protein / Q000502:physiology; D005434:Flow Cytometry; D053804:Granzymes / Q000502:physiology*; D007156:Immunologic Memory / Q000276:immunology*; D008565:Membrane Proteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D052899:Pore Forming Cytotoxic Proteins / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015843:Serpins / Q000502:physiology*; D016038:Skin Transplantation; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D053222:Fas Ligand Protein; D008565:Membrane Proteins; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger; D015843:Serpins; C483886:perforin, mouse; D053804:Granzymes; C106610:Serpinb9 protein, mouse