Relative Diabetogenic Properties of Islet-Specific Tc1 and Tc2 Cells in Immunocompetent Hosts

• DOI: 10.4049/jimmunol.165.11.6314
• Publication Date: 2014-04-22T02:44:50Z
• Authors: Csaba Vizler; Nadège Bercovici; Agnès Heurtier; Nathalie Pardigon; Karine Goude; Karine Bailly; Christophe Combad...; Roland S Liblau
• Keywords: MESH: T-Lymphocyte Subsets/transplantation; 0301 basic medicine; MESH: Diabetes Mellitus, Type 1/pathology; Epitopes, T-Lymphocyte; Hemagglutinin Glycoproteins, Influenza Virus; MESH: Promoter Regions, Genetic/immunology; CD8-Positive T-Lymphocytes; Lymphocyte Activation; [SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity; MESH: Pancreas/pathology; Mice; Cell Movement; T-Lymphocyte Subsets; MESH: Islets of Langerhans/immunology; Tumor Cells, Cultured; Insulin; MESH: Animals; Promoter Regions, Genetic; Cells, Cultured; Mice, Inbred BALB C; MESH: Cell Movement/genetics; MESH: Diabetes Mellitus, Type 1/immunology; MESH: Epitopes, T-Lymphocyte/immunology; MESH: CD8-Positive T-Lymphocytes/transplantation; Cell Differentiation; Adoptive Transfer; 3. Good health; MESH: CD8-Positive T-Lymphocytes/immunology; MESH: Diabetes Mellitus, Type 1/genetics; MESH: Cells, Cultured; MESH: Rats; MESH: Mice, Transgenic; MESH: Mice, Inbred BALB C; MESH: Cell Movement/immunology; Mice, Transgenic; MESH: CD8-Positive T-Lymphocytes/pathology; Islets of Langerhans; 03 medical and health sciences; MESH: Lymphocyte Activation/genetics; MESH: T-Lymphocyte Subsets/immunology; Animals; MESH: Tumor Cells, Cultured; MESH: Insulin/genetics; MESH: Mice; Pancreas; MESH: T-Lymphocyte Subsets/pathology; MESH: Diabetes Mellitus, Type 1/etiology; MESH: Islets of Langerhans/pathology; MESH: Cell Differentiation/genetics; Rats; MESH: Adoptive Transfer; Diabetes Mellitus, Type 1; MESH: Pancreas/immunology; MESH: Hemagglutinin Glycoproteins, Influenza Virus/genetics; MESH: Cell Differentiation/immunology

Abstract CD8+ T cells are important effectors, as well as regulators, of organ-specific autoimmunity. Compared with Tc1-type CD8+ cells, Tc2 cells have impaired anti-viral and anti-tumor effector functions, although no data are yet available on their pathogenic role in autoimmunity. Our aim was to explore the role of autoreactive Tc1 and Tc2 cells in autoimmune diabetes. We set up an adoptive transfer model in which the recipients were transgenic mice expressing influenza virus hemagglutinin (HA) specifically in their pancreatic β islet cells (rat insulin promoter-HA mice) and islet-specific Tc1 and Tc2 cells were generated in vitro from HA-specific CD8+ cells of TCR transgenic mice (CL4-TCR mice). One million Tc1 cells, differentiated in vitro in the presence of IL-12, transferred diabetes in 100% of nonirradiated adult rat insulin promoter-HA recipients; the 50% diabetogenic dose was 5 × 105. Highly polarized Tc2 cells generated in the presence of IL-4, IL-10, and anti-IFN-γ mAb had a relatively low, but definite, diabetogenic potential. Thus, 5 × 106 Tc2 cells caused diabetes in 6 of 18 recipients, while the same dose of naive CD8+ cells did not cause diabetes. Looking for the cause of the different diabetogenic potential of Tc1 and Tc2 cells, we found that Tc2 cells are at least as cytotoxic as Tc1 cells but their accumulation in the pancreas is slower, a possible consequence of differential chemokine receptor expression. The diabetogenicity of autoreactive Tc2 cells, most likely caused by their cytotoxic activity, precludes their therapeutic use as regulators of autoimmunity.