title: T cell receptor transgenic lymphocytes infiltrating murine tumors are not induced to express foxp3.
abstract: Regulatory T cells (Treg) that express the transcription factor Foxp3 are enriched within a broad range of murine and human solid tumors. The ontogeny of these Foxp3 Tregs - selective accumulation or proliferation of natural thymus-derived Treg (nTreg) or induced Treg (iTreg) converted in the periphery from naïve T cells - is not known. We used several strains of mice in which Foxp3 and EGFP are coordinately expressed to address this issue. We confirmed that Foxp3-positive CD4 T cells are enriched among tumor-infiltrating lymphocytes (TIL) and splenocytes (SPL) in B16 murine melanoma-bearing C57BL/6 Foxp3(EGFP) mice. OT-II Foxp3(EGFP) mice are essentially devoid of nTreg, having transgenic CD4 T cells that recognize a class II-restricted epitope derived from ovalbumin; Foxp3 expression could not be detected in TIL or SPL in these mice when implanted with ovalbumin-transfected B16 tumor (B16-OVA). Likewise, TIL isolated from B16 tumors implanted in Pmel-1 Foxp3(EGFP) mice, whose CD8 T cells recognize a class I-restricted gp100 epitope, were not induced to express Foxp3. All of these T cell populations - wild-type CD4, pmel CD8 and OTII CD4 - could be induced in vitro to express Foxp3 by engagement of their T cell receptor (TCR) and exposure to transforming growth factor β (TGFβ). B16 melanoma produces TGFβ and both pmel CD8 and OTII CD4 express TCR that should be engaged within B16 and B16-OVA respectively. Thus, CD8 and CD4 transgenic T cells in these animal models failed to undergo peripheral induction of Foxp3 in a tumor microenvironment.
authors: Departments of Surgery, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Jon G
authors: JG
authors: Quatromoni
authors: Lilah F
authors: LF
authors: Morris
authors: Timothy R
authors: TR
authors: Donahue
authors: Yue
authors: Y
authors: Wang
authors: William
authors: W
authors: McBride
authors: Talal
authors: T
authors: Chatila
authors: James S
authors: JS
authors: Economou
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D051858:Forkhead Transcription Factors / Q000096:biosynthesis* / Q000235:genetics / Q000276:immunology; D016219:Immunotherapy, Adoptive / Q000379:methods*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011948:Receptors, Antigen, T-Cell