Requirement for both H-2Db and H-2Kd for the induction of diabetes by the promiscuous CD8+ T cell clonotype AI4

Toshiyuki Takaki; Scott M Lieberman; Thomas M Holl; Bingye Han; Pere Santamaria; David V Serreze; Teresa P DiLorenzo

doi:10.4049/jimmunol.173.4.2530

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Requirement for both H-2Db and H-2Kd for the induction of diabetes by the promiscuous CD8+ T cell clonotype AI4

Journal article

Open access

Peer reviewed

Requirement for both H-2Db and H-2Kd for the induction of diabetes by the promiscuous CD8+ T cell clonotype AI4

Toshiyuki Takaki, Scott M Lieberman, Thomas M Holl, Bingye Han, Pere Santamaria, David V Serreze and Teresa P DiLorenzo

The Journal of immunology (1950), Vol.173(4), pp.2530-2541

08/15/2004

DOI: 10.4049/jimmunol.173.4.2530

PMID: 15294969

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Abstract

The NOD mouse is a model for autoimmune type 1 diabetes in humans. CD8(+) T cells are essential for the destruction of the insulin-producing pancreatic beta cells characterizing this disease. AI4 is a pathogenic CD8(+) T cell clone, isolated from the islets of a 5-wk-old female NOD mouse, which is capable of mediating overt diabetes in the absence of CD4(+) T cell help. Recent studies using MHC-congenic NOD mice revealed marked promiscuity of the AI4 TCR, as the selection of this clonotype can be influenced by multiple MHC molecules, including some class II variants. The present work was designed, in part, to determine whether similar promiscuity also characterizes the effector function of mature AI4 CTL. Using splenocyte and bone marrow disease transfer models and in vitro islet-killing assays, we report that efficient recognition and destruction of beta cells by AI4 requires the beta cells to simultaneously express both H-2D(b) and H-2K(d) class I MHC molecules. The ability of the AI4 TCR to interact with both H-2D(b) and H-2K(d) was confirmed using recombinant peptide libraries. This approach also allowed us to define a mimotope peptide recognized by AI4 in an H-2D(b)-restricted manner. Using ELISPOT and mimotope/H-2D(b) tetramer analyses, we demonstrate for the first time that AI4 represents a readily detectable T cell population in the islet infiltrates of prediabetic NOD mice. Our identification of a ligand for AI4-like T cells will facilitate further characterization and manipulation of this pathogenic and promiscuous T cell population.

Peptides - immunology

Diabetes Mellitus, Type 1 - genetics

Islets of Langerhans - immunology

Histocompatibility Antigen H-2D

Mice, Transgenic

Adoptive Transfer

Peptide Library

H-2 Antigens - immunology

Animals

Flow Cytometry

H-2 Antigens - genetics

Mice, Inbred NOD

Clone Cells

Mice

Diabetes Mellitus, Type 1 - immunology

CD8-Positive T-Lymphocytes - immunology

Cytotoxicity, Immunologic

Disease Models, Animal

Details

Title: Subtitle: Requirement for both H-2Db and H-2Kd for the induction of diabetes by the promiscuous CD8+ T cell clonotype AI4
Creators: Toshiyuki Takaki - Departments of Microbiology and Immunology, and Medicine (Division of Endocrinology), Albert Einstein College of Medicine, Bronx, NY 10461, USA
Scott M Lieberman
Thomas M Holl
Bingye Han
Pere Santamaria
David V Serreze
Teresa P DiLorenzo
Resource Type: Journal article
Publication Details: The Journal of immunology (1950), Vol.173(4), pp.2530-2541
DOI: 10.4049/jimmunol.173.4.2530
PMID: 15294969
ISSN: 0022-1767
eISSN: 1550-6606
Grant note: DK64315 / NIDDK NIH HHS DK46266 / NIDDK NIH HHS CA13330 / NCI NIH HHS DK20541 / NIDDK NIH HHS DK52956 / NIDDK NIH HHS GM07288 / NIGMS NIH HHS DK51090 / NIDDK NIH HHS
Language: English
Date published: 08/15/2004
Academic Unit: Stead Family Department of Pediatrics; Rheumatology, Allergy, and Immunology
Record Identifier: 9984093331702771

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