In vivo diabetogenic action of CD4⁺ T lymphocytes requires Fas expression and is independent of IL‐1 and IL‐18

Abstract

CD4+ T lymphocytes are required to induce spontaneous autoimmune diabetes in the NOD (Non Obese Diabetic) mouse. Since pancreatic β cells upregulate Fas expression upon exposure to pro-inflammatory cytokines, we studied whether the diabetogenic action of CD4+ T lymphocytes depends on Fas expression on target cells. We assayed the diabetogenic capacity of NOD spleen CD4+ T lymphocytes when adoptively transferred into a NOD mouse model combining: a) Fas-deficiency, b) FasL-deficiency, and c) the SCID mutation. We found that CD4+ T lymphocytes require Fas expression in the recipients’ target cells to induce diabetes. IL-1β has been described as a key cytokine involved in Fas up-regulation on mouse β cells. We addressed whether CD4+ T cells require IL-1β to induce diabetes. We also studied spontaneous diabetes onset in NOD/ICE (Interleukin-1 Converting Enzyme) deficient mice, in NOD/IL-1β deficient mice, and CD4+ T cell-adoptively transferred diabetes into NOD/SCID IL-1β-deficient mice. Neither IL-1β nor IL-18 are required for either spontaneous or CD4+ T-cell adoptively transferred diabetes. We conclude that CD4+ T cell-mediated β cell damage in autoimmune diabetes depends on Fas expression, but not on IL-1β, unveiling the existing redundancy regarding the cytokines involved in Fas upregulation on NOD β cells in vivo.

NLRP3 deficiency protects from type 1 diabetes through the regulation of chemotaxis into the pancreatic islets

“…In addition to IL-1β, NLRP3 also activates IL-18. The role of IL-18 in T1D is controversial; some studies suggest that IL-18 promotes T1D development (37), possibly through inducing diabetogenic T-cell expansion in NOD mice (38), whereas other studies, including our own, indicate that IL-18 is not required for T1D development (18,19). However, the role of IL-18 in diabetes protection in the NLRP3-deficient NOD mice is not clear.…”

“…Nevertheless, the role of the inflammasome pathway in the pathogenesis of T1D is unclear. Although caspase-1 or IL-1β deficiency did not protect NOD mice from T1D (18,19), IL-1 blockade showed a synergistic protective effect when combined with anti-CD3 therapy for T1D in a mouse model (20). Interestingly, recent genetic association studies suggested that polymorphisms in inflammasome genes might be involved in the predisposition to T1D.…”

Fas/Fas-Ligand Interaction As a Mechanism of Immune Homeostasis and β-Cell Cytotoxicity: Enforcement Rather Than Neutralization for Treatment of Type 1 Diabetes

“…Induced Fas transcription and modulation of expression is caused by a number of proinflammatory cytokines including IL-1α, IL-1β, IFNγ, nitric oxide (NO), and TNF-α that synergize with Fas as effector mechanisms of β-cell destruction (37, 41). Furthermore, both Fas expression induced by IL-1β (42) independent of NFκB activation (43, 44) and islet sensitization to apoptosis (45, 46) also evolve as direct consequences of hyperglycemia. The vast changes in transcriptomes and expression profiles of the inflamed islets may be viewed as an effort of the tissue to sustain insulin production and increase β-cell mass.…”

A Fully Automated Primary Screening System for the Discovery of Therapeutic Antibodies Directly from B Cells

“…[5][6][7] The inefficiency of the hybridoma and phage methods provided us with an opportunity to change the way we make monoclonal antibodies. The Antibody Discovery Group at UCB developed a B cell culture method, 8,9 linked to homogeneous assays and a sensitive PCR process to clone out the cognate antibody V region genes. 10 This methodology has given us a greater ability to screen the antibody repertoire of an immunized animal, allowing the screening of more than a billion B cells in a campaign over 2 weeks, to select a panel of antibodies, that after further in vitro and in vivo secondary screening, have the potential to be therapeutic antibody candidates.…”