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Arthritis Research (1)
Journal of immunology (Baltimore, Md. : 1950) (1)
Brand, David D. (1)
Guedez, Yajaira B (1)
Latham, Kary (1)
Latham, Kary A. (1)
Miller, David C. (1)
Qian, Zhaohui (1)
Rosloniec, Edward F (1)
Rosloniec, Edward F. (1)
Whittington, Karen B. (1)
Year of Publication
Engineered Tregulatory cells co-expressing MHC class II:peptide complexes are efficient inhibitors of autoimmune T cell function and prevent the development of autoimmune arthritis
Whittington, Karen B.
Miller, David C.
Brand, David D.
Rosloniec, Edward F.
Journal of immunology (Baltimore, Md. : 1950)
Treg cells are critical homeostatic components in preventing the development of autoimmunity, and are a major focus for their therapeutic potential for autoimmune diseases. In order to enhance the efficacy of Treg cells in adoptive therapy, we developed a strategy for generating engineered Tregs that have the capacity to target autoimmune T cells in an antigen specific manner. Using a retroviral expression system encoding Foxp3 and HLA-DR1 covalently linked to the immunodominant peptide of the autoantigen type II collagen (DR1-CII), naïve T cells were engineered to become Treg cells that express DR1-CII complexes on their surface. When these cells were tested for their ability to prevent the development of collagen induced arthritis, both the engineered DR1-CII-Foxp3 and Foxp3 only Treg cells significantly reduced the severity and incidence of disease. However, the mechanism buy which these two populations of Treg cells inhibited disease differed significantly. Disease inhibition by the DR1-CII-Foxp3 Treg cells was accompanied by significantly lower numbers of autoimmune CII-specific T cells in vivo and lower levels of autoantibodies in comparison to engineered Tregs expressing Foxp3 alone. Additionally, the numbers of IFN-γ and IL-17 expressing T cells in mice treated with DR1-CII-Foxp3 Tregs were also significantly reduced in comparison to mice treated with Foxp3 engineered Treg cells or vector control cells. These data indicate that the co-expression of class II autoantigen-peptide complexes on Treg cells provides these cells with a distinct capacity to regulate autoimmune T cell responses that differs from that used by conventional Treg cells.
Paradoxical roles of IFN-γ in models of Th1-mediated autoimmunity
Rosloniec, Edward F
Guedez, Yajaira B
T-cell responses to antigens are classified on the basis of the cytokines they produce as either Th1 (IFN-γ, IL-2) or Th2 (IL-4, IL-10), with these Th types being indicative of either cell-mediated or antibody-mediated responses, respectively. Using this classification, T-cell responses in MHC-class-II-restricted autoimmune diseases appear to be predominantly of the Th1 type, based on the presence of high levels of IFN-γ. This simplistic classification has recently been challenged, however, as disease incidence and severity are frequently elevated in animals that have a deficient IFN-γ response. The recent data discussed here indicate that the cytokine circuits involved in the regulation of cell-mediated and humoral immune responses during the development of autoimmune arthritis are more complex than originally proposed; perhaps our characterization of autoimmune responses as strictly Th1 or Th2 is overly simplistic, especially as it pertains to the role of IFN-γ.
arthritis; autoimmunity; cytokines; IFN-γ
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