title: CD69+ CD4+ CD25- T cells, a new subset of regulatory T cells, suppress T cell proliferation through membrane-bound TGF-beta 1.
abstract: The underlying mechanisms of tumor-induced immune suppression need to be fully understood. Regulatory T (Treg) cells have been shown to play an important role in tumor immune escape. Until now, many subsets of Treg cells have been described that can suppress T cell response via different mechanisms. CD69 is generally regarded as one of the activating markers; however, recent studies show that CD69 may exert regulatory function in the immune response. In this study, we have identified tumor-induced CD69(+)CD4(+)CD25(-) T cells as a new subset of CD4(+) Treg cells. CD69(+)CD4(+)CD25(-) T cells increase dramatically along tumor progression, with up to 40% of CD4(+) T cells in the advanced tumor-bearing mice. Distinct from the previously described CD4(+) Treg cell subsets, CD69(+)CD4(+)CD25(-) T cells express high CD122, but they do not express Foxp3 and secrete IL-10, TGF-beta1, IL-2, and IFN-gamma. CD69(+)CD4(+)CD25(-) T cells are hyporesponsive and can suppress CD4(+) T cell proliferation in a cell-cell contact manner. Interestingly, the fixed CD69(+)CD4(+)CD25(-) T cells still have suppressive activity, and neutralizing Abs against TGF-beta1 can block their suppressive activity. We found that CD69(+)CD4(+)CD25(-) T cells express membrane-bound TGF-beta1, which mediates suppression of T cell proliferation. Furthermore, engagement of CD69 maintains high expression of membrane-bound TGF-beta1 on CD69(+)CD4(+)CD25(-) T cells via ERK activation. Our results demonstrate that CD69(+)CD4(+)CD25(-) T cells act as a new subset of regulatory CD4(+) T cells, with distinct characteristics of negative expression of Foxp3, no secretion of IL-10, but high expression of CD122 and membrane-bound TGF-beta1. Our data contribute to the better understanding of mechanisms for tumor immune escape.
authors.affiliation: National Key Laboratory of Medical Immunology, Institute of Immunology, Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Yanmei
authors.initials: Y
authors.lastname: Han
authors.forename: Qiuli
authors.initials: Q
authors.lastname: Guo
authors.forename: Minggang
authors.initials: M
authors.lastname: Zhang
authors.forename: Zhubo
authors.initials: Z
authors.lastname: Chen
authors.forename: Xuetao
authors.initials: X
authors.lastname: Cao
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis* / Q000502:physiology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis* / Q000502:physiology; D015704:CD4 Antigens / Q000096:biosynthesis*; D018827:Carcinoma, Lewis Lung / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D018920:Coculture Techniques; D018450:Disease Progression; D004789:Enzyme Activation / Q000276:immunology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006131:Growth Inhibitors / Q000502:physiology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D037181:Lectins, C-Type; D008175:Lung Neoplasms / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008546:Melanoma, Experimental / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011485:Protein Binding / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D053773:Transforming Growth Factor beta1 / Q000502:physiology*; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D015704:CD4 Antigens; D048049:Extracellular Signal-Regulated MAP Kinases; D006131:Growth Inhibitors; D053645:Interleukin-2 Receptor alpha Subunit; D037181:Lectins, C-Type; D008565:Membrane Proteins; D053773:Transforming Growth Factor beta1; D000099192:CD69 Antigens