title: Co-expression of TNFR2 and CD25 identifies more of the functional CD4+FOXP3+ regulatory T cells in human peripheral blood.
abstract: Previously, we found that co-expression of CD25 and TNFR2 identified the most suppressive subset of mouse Treg. In this study, we report that human peripheral blood (PB) FOXP3(+) cells present in CD25(high), CD25(low) and even CD25(-) subsets of CD4(+) cells expressed high levels of TNFR2. Consequently, TNFR2-expressing CD4(+)CD25(+) Treg included all of the FOXP3(+) cells present in the CD4(+)CD25(high) subset as well as a substantial proportion of the FOXP3(+) cells present in the CD4(+)CD25(low) subset. Flow cytometric analysis of PB identified five-fold more Treg, determined by FOXP3 expression, in the CD4(+)CD25(+)TNFR2(+) subset than in the CD4(+)CD25(high) subset. In addition, similar levels of FOXP3(+) cells were identified in both the CD4(+)CD25(+)TNFR2(+) and CD4(+)CD25(+)CD127(low/-) subsets. Furthermore, the CD4(+)CD25(+)TNFR2(+) subset expressed high levels of CTLA-4, CD45RO, CCR4 and low levels of CD45RA and CD127, a phenotype characteristic of Treg. Upon TCR stimulation, human PB CD4(+)CD25(+)TNFR2(+) cells were anergic and markedly inhibited the proliferation and cytokine production of co-cultured T-responder cells. In contrast, CD4(+)CD25(+)TNFR2(-) and CD4(+)CD25(-)TNFR2(+) T cells did not show inhibitory activity. As some non-Treg express TNFR2, the combination of CD25 and TNFR2 must be used to identify a larger population of human Treg, a population that may prove to be of diagnostic and therapeutic benefit in cancer and autoimmune diseases.
authors.affiliation: Basic Science Program, Laboratory of Molecular Immunoregulation, SAIC-Frederick, Inc., NCI-Frederick, Frederick, MD 21702-1201, USA. chenxin@mail.nih.gov
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Subleski
authors.forename: Ryoko
authors.initials: R
authors.lastname: Hamano
authors.forename: O M Zack
authors.initials: OM
authors.lastname: Howard
authors.forename: Robert H
authors.initials: RH
authors.lastname: Wiltrout
authors.forename: Joost J
authors.initials: JJ
authors.lastname: Oppenheim
mesh_terms: D000328:Adult; D017951:Antigen Presentation; D015703:Antigens, CD / Q000032:analysis; D060908:CTLA-4 Antigen; D002478:Cells, Cultured / Q000276:immunology / Q000378:metabolism; D018920:Coculture Techniques; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000032:analysis*; D006801:Humans; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis / Q000096:biosynthesis*; D053699:Interleukin-7 Receptor alpha Subunit / Q000032:analysis; D017493:Leukocyte Common Antigens / Q000032:analysis; D008213:Lymphocyte Activation / Q000187:drug effects; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000032:analysis / Q000096:biosynthesis*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000145:classification* / Q000276:immunology / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit; D053699:Interleukin-7 Receptor alpha Subunit; D011948:Receptors, Antigen, T-Cell; D047889:Receptors, Tumor Necrosis Factor, Type II; D007371:Interferon-gamma; D017493:Leukocyte Common Antigens