title: Neuropilin-1highCD4⁺CD25⁺ Regulatory T Cells Exhibit Primary Negative Immunoregulation in Sepsis.
abstract: Regulatory T cells (Tregs) appear to be involved in sepsis-induced immune dysfunction; neuropilin-1 (Nrp-1) was identified as a surface marker for CD4(+)CD25(+)Tregs. In the current study, we investigated the negative immunoregulation of Nrp-1(high)CD4(+)CD25(+)Tregs and the potential therapeutic value of Nrp-1 in sepsis. Splenic CD4(+)CD25(+)Tregs from cecal ligation and puncture (CLP) mouse models were further segregated into Nrp-1(high)Tregs and Nrp-1(low)Tregs; they were cocultured with CD4(+)CD25(-)  T cells. The expression of forkhead/winged helix transcription factor-3 (Foxp-3), cytotoxic T-lymphocyte associated antigen-4 (CTLA-4), membrane associated transforming growth factor-β (TGF-β(m+)), apoptotic rate, and secretive ability [including TGF-β and interleukin-10 (IL-10)] for various types of Tregs, as well as the immunosuppressive ability of Tregs on CD4(+)CD25(-)  T cells, were determined. Meanwhile, the impact of recombinant Nrp-1 polyclonal antibody on the demethylation of Foxp-3-TSDR (Treg-specific demethylated region) was measured in in vitro study. Sepsis per se markedly promoted the expression of Nrp-1 of CD4(+)CD25(+)Tregs. Foxp-3/CTLA-4/TGF-β(m+) of Nrp-1(high)Tregs were upregulated by septic challenge. Nrp-1(high)Tregs showed strong resilience to apoptosis and secretive ability and the strongest immunosuppressive ability on CD4(+)CD25(-)  T cells. In the presence of lipopolysaccharide (LPS), the recombinant Nrp-1 polyclonal antibody reduced the demethylation of Foxp-3-TSDR. Nrp-1(high)Tregs might reveal primary negative immunoregulation in sepsis; Nrp-1 could represent a new potential therapeutic target for the study of immune regulation in sepsis.
authors.affiliation: Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, China.
authors.forename: Yu-Lei
authors.initials: YL
authors.lastname: Gao
authors.affiliation: Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, China.
authors.forename: Yan-Fen
authors.initials: YF
authors.lastname: Chai
authors.affiliation: Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, China.
authors.forename: An-Long
authors.initials: AL
authors.lastname: Qi
authors.affiliation: Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, China.
authors.forename: Yan-Cun
authors.initials: YC
authors.lastname: Liu
authors.affiliation: Trauma Research Center, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing 100048, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Dong
authors.affiliation: Department of Emergency Medicine, Tianjin Medical University General Hospital, Tianjin 300052, China.
authors.forename: Li-Jun
authors.initials: LJ
authors.lastname: Wang
authors.affiliation: Trauma Research Center, First Hospital Affiliated to the Chinese PLA General Hospital, Beijing 100048, China; State Key Laboratory of Kidney Disease, The Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Yong-Ming
authors.initials: YM
authors.lastname: Yao
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D060908:CTLA-4 Antigen / Q000378:metabolism; D004195:Disease Models, Animal; D051858:Forkhead Transcription Factors / Q000378:metabolism; D016753:Interleukin-10 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D039921:Neuropilins / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism; D018805:Sepsis / Q000276:immunology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D060908:CTLA-4 Antigen; D051858:Forkhead Transcription Factors; C432917:Foxp1 protein, mouse; C508609:IL10 protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D039921:Neuropilins; D012097:Repressor Proteins; D016212:Transforming Growth Factor beta; D016753:Interleukin-10