title: Eliminating roles for T-bet and IL-2 but revealing superior activation and proliferation as mechanisms underpinning dominance of regulatory T cells in tumors.
abstract: Foxp3(+) regulatory T cells (Tregs) are often highly enriched within the tumor-infiltrating T cell pool. Using a well-characterised model of carcinogen-induced fibrosarcomas we show that the enriched tumor-infiltrating Treg population comprises largely of CXCR3(+) T-bet(+) 'TH1-like' Tregs which are thymus-derived Helios(+) cells. Whilst IL-2 maintains homeostatic ratios of Tregs in lymphoid organs, we found that the perturbation in Treg frequencies in tumors is IL-2 independent. Moreover, we show that the TH1 phenotype of tumor-infiltrating Tregs is dispensable for their ability to influence tumor progression. We did however find that unlike Tconvs, the majority of intra-tumoral Tregs express the activation markers CD69, CD25, ICOS, CD103 and CTLA4 and are significantly more proliferative than Tconvs. Moreover, we have found that CD69(+) Tregs are more suppressive than their CD69- counterparts. Collectively, these data indicate superior activation of Tregs in the tumor microenvironment, promoting their suppressive ability and selective proliferation at this site.
authors.affiliation: Institute of Infection Immunity and Biochemistry, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK.
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Colbeck
authors.affiliation: Institute of Infection Immunity and Biochemistry, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK.
authors.forename: James P
authors.initials: JP
authors.lastname: Hindley
authors.affiliation: Institute of Infection Immunity and Biochemistry, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Smart
authors.affiliation: Institute of Infection Immunity and Biochemistry, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Jones
authors.affiliation: Institute of Infection Immunity and Biochemistry, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK.
authors.forename: Anja
authors.initials: A
authors.lastname: Bloom
authors.affiliation: Institute of Infection Immunity and Biochemistry, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK.
authors.forename: Hayley
authors.initials: H
authors.lastname: Bridgeman
authors.affiliation: MRC Centre for Inflammation Research, Centre for Multiple Sclerosis Research and Centre for Immunity Infection and Evolution, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Rhoanne C
authors.initials: RC
authors.lastname: McPherson
authors.affiliation: MRC Centre for Inflammation Research, Centre for Multiple Sclerosis Research and Centre for Immunity Infection and Evolution, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Darryl G
authors.initials: DG
authors.lastname: Turner
authors.affiliation: Institute of Infection Immunity and Biochemistry, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK.
authors.forename: Kristin
authors.initials: K
authors.lastname: Ladell
authors.affiliation: Institute of Infection Immunity and Biochemistry, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.affiliation: MRC Centre for Inflammation Research, Centre for Multiple Sclerosis Research and Centre for Immunity Infection and Evolution, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Richard A
authors.initials: RA
authors.lastname: O'Connor
authors.affiliation: MRC Centre for Inflammation Research, Centre for Multiple Sclerosis Research and Centre for Immunity Infection and Evolution, University of Edinburgh, Edinburgh EH16 4TJ, UK.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Anderton
authors.affiliation: Institute of Infection Immunity and Biochemistry, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Godkin
authors.affiliation: Institute of Infection Immunity and Biochemistry, Cardiff University School of Medicine, Cardiff, CF14 4XN, UK.
authors.forename: Awen M
authors.initials: AM
authors.lastname: Gallimore
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000276:immunology / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D005354:Fibrosarcoma / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D018836:Inflammation Mediators / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000187:drug effects; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D008748:Methylcholanthrene; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D012513:Sarcoma, Experimental / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D020825:T-Box Domain Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D059016:Tumor Microenvironment; D000098815:T-bet Transcription Factor
chemical_list: D000911:Antibodies, Monoclonal; D014408:Biomarkers, Tumor; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D018836:Inflammation Mediators; D007376:Interleukin-2; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D008748:Methylcholanthrene
keywords: CD69; Immune response; Immunity; Immunology Section; T-bet; Treg; cancer; proliferation