IL-35-mediated induction of a potent regulatory T cell population

Abstract

Regulatory T cells (Tregs) play a critical role in the maintenance of immunological self-tolerance. Naïve human or murine T cell treatment with the inhibitory cytokine IL-35 induces a regulatory population, termed iTR35, that mediates suppression via IL-35, but not IL-10 or TGFβ, neither express nor require Foxp3, are strongly suppressive in five in vivo models, and exhibit in vivo stability. Treg-mediated suppression induces iTR35 generation in an IL-35- and IL-10-dependent manner in vitro, and in inflammatory conditions in vivo in Trichuris-infected intestines and within the tumor microenvironment, where they appear to contribute to the regulatory milieu. iTR35 may constitute a key mediator of infectious tolerance, may contribute to Treg-mediated tumor progression, and ex vivo generated iTR35 may possess therapeutic utility.

Transient depletion of regulatory T cells in transgenic mice reactivates virus-specific CD8 + T cells and reduces chronic retroviral set points

“…Injection of DT into these animals specifically eliminates Foxp3-expressing Tregs, although leaving the overall composition of other lymphocyte subsets intact (8,9). Foxp3-negative Tregs, which have been found in mice (10,11), cannot be depleted in this model.…”

Mucosal Administration of Collagen V Ameliorates the Atherosclerotic Plaque Burden by Inducing Interleukin 35-dependent Tolerance

“…Five-week-old mice were inoculated intranasally with 4 g of bovine col(V) (a gift from ImmuneWorks Inc.), 4 g of col(I) (PureCol, Advanced BioMatrix), or PBS every other day for 2 weeks while on normal chow (Harlan Teklad 8604) and then placed on a "Western" high-fat (20 gram percent), 1.25% cholesterol diet (D12108C, Research Diets) for 14 or 24 weeks and inoculated two times per week for the duration of the experiment. A subset of the col(V)-treated mice for the 24-week study was subjected to intraperitoneal injection with 100 g of murine anti-mouse Ebi3 antibody (antibody V1.4C4.22 (25)) or with isotype-matched control murine IgG2b at 12 weeks subsequent to the start of the Western diet and then with 50 g of anti-EBi3 or IgG2b once per week until sacrifice. Two weeks prior to sacrifice, all mice were immunized subcutaneously in the inguinal region with 1.5 limits of flocculation tetanus toxoid and diphtheria (TT/DT) pediatric vaccine (Sanofi-Aventis Pasteur).…”

“…Bovine col(V) (ImmuneWorks Inc.) and col(I) (PureCol, Advanced BioMatrix) were tested at 20 g each. Cytokines were neutralized by coinjection of 1 g of antibodies against mouse IFN-␥, IL-17A, TGF-␤ (BD Biosciences), IL-10, IL-27 p28, IL-12/IL-35 p35 (R&D Systems), and Ebi3 (antibody V1.4C4.22) (25).…”

CD4+VEGFR1HIGH T cell as a novel Treg subset regulates inflammatory bowel disease in lymphopenic mice

“…4 Since then, many phenotypically distinct CD4 1 Treg subsets have been identified, including Foxp3 1 , IL-10-secreting Tr1, transforming growth factor (TGF)-b-secreting Th3, and Foxp3 neg iT(R)35 cells. [5][6][7][8][9][10][11][12][13][14] The mechanisms of Treg function generally include the following: suppression by inhibitory cytokines, such as interleukin-10 (IL-10), TGF-b, and IL-35; suppression of effector T cells by IL-2 depletion or generation of pericellular adenosine; suppression by targeting dendritic cells (DCs) through cytotoxic T lymphocyte-associated antigen (CTLA), indoleamine 2,3-dioxygenase, and lymphocyte-activation gene 3; and cytolysis by secretion of granzyme-A and -B. 15,16 Vascular endothelial growth factor receptor-1 (VEGFR1) has seven immunoglobulin (Ig)-like domains in the extracellular domain (ECD), a single transmembrane region and a consensus tyrosine kinase sequence.…”