title: Analysis of the T-cell receptor repertoires of tumor-infiltrating conventional and regulatory T cells reveals no evidence for conversion in carcinogen-induced tumors.
abstract: A significant enrichment of CD4(+)Foxp3(+) T cells (regulatory T cells, Treg) is frequently observed in murine and human carcinomas. As Tregs can limit effective antitumor immune responses, thereby promoting tumor progression, it is important that the mechanisms underpinning intratumoral accumulation of Tregs are identified. Because of evidence gathered mostly in vitro, the conversion of conventional T cells (Tconv) into Tregs has been proposed as one such mechanism. We assessed the contribution of conversion in vivo by analyzing the TCR (T-cell receptor) repertoires of Tconvs and Tregs in carcinogen-induced tumors in mice. Our results indicate that the TCR repertoires of Tregs and Tconvs within tumor-infiltrating lymphocytes (TIL) are largely distinct. Indeed, the cell population with the greatest degree of repertoire similarity with tumor-infiltrating Tregs was the Treg population from the tumor-draining lymph node. These findings demonstrate that conversion of Tconvs does not contribute significantly to the accumulation of tumor-infiltrating Tregs; rather, Tconvs and Tregs arise from different populations with unique TCR repertoires. Enrichment of Tregs within TILs most likely, therefore, reflects differences in the way that Tregs and Tconvs are influenced by the tumor microenvironment. Elucidating the nature of these influences may indicate how the balance between tumor-infiltrating Tregs and Tconvs can be manipulated for therapeutic purposes.
authors.affiliation: Department of Infection, Immunity and Biochemistry, Cardiff University School of Medicine, Cardiff, Wales, United Kingdom. hindleyjp@cf.ac.uk
authors.forename: James P
authors.initials: JP
authors.lastname: Hindley
authors.forename: Cristina
authors.initials: C
authors.lastname: Ferreira
authors.forename: Emma
authors.initials: E
authors.lastname: Jones
authors.forename: Sarah N
authors.initials: SN
authors.lastname: Lauder
authors.forename: Kristin
authors.initials: K
authors.lastname: Ladell
authors.forename: Katherine K
authors.initials: KK
authors.lastname: Wynn
authors.forename: Gareth J
authors.initials: GJ
authors.lastname: Betts
authors.forename: Yogesh
authors.initials: Y
authors.lastname: Singh
authors.forename: David A
authors.initials: DA
authors.lastname: Price
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Godkin
authors.forename: Julian
authors.initials: J
authors.lastname: Dyson
authors.forename: Awen
authors.initials: A
authors.lastname: Gallimore
mesh_terms: D000818:Animals; D002273:Carcinogens; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008748:Methylcholanthrene; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D002273:Carcinogens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011948:Receptors, Antigen, T-Cell; D008748:Methylcholanthrene