Defective CD8+ T cell peripheral tolerance in nonobese diabetic mice

Area of Science:

• Immunology
• Autoimmunity
• Diabetes Research

Background:

• Nonobese diabetic (NOD) mice spontaneously develop autoimmune diabetes involving CD4+ and CD8+ T cells.
• Previous research indicated CD4+ T cell reactivity to self-antigens (self-Ags) in NOD mice.
• The maintenance of CD8+ T cell tolerance to self-Ags in NOD mice remained unevaluated.

Purpose of the Study:

• To investigate CD8+ T cell tolerance to a model pancreatic autoantigen, hemagglutinin (HA), in NOD mice.
• To determine if NOD mice lacking peripheral tolerance exhibit high-avidity CD8+ T cells specific for islet autoantigens.
• To assess the role of these autoreactive CD8+ T cells in the development of autoimmune diabetes.

Main Methods:

• Utilized InsHA transgenic mice, where pancreatic beta cells express the hemagglutinin (HA) molecule.
• Assessed CD8+ T cell avidity for HA using tetramer (K(d)HA) binding and dose titration.
• Performed adoptive transfer of autoreactive CD8+ T cells into NOD-InsHA recipient mice.

Main Results:

• NOD-InsHA mice demonstrated a deficiency in peripheral CD8+ T cell tolerance to the HA autoantigen.
• High-avidity CD8+ T cells specific for HA were identified in NOD-InsHA mice.
• Adoptive transfer of these autoreactive CD8+ T cells rapidly induced diabetes in recipient mice.

Conclusions:

• NOD mice exhibit a failure to establish or maintain peripheral tolerance in the CD8+ T cell repertoire towards islet autoantigens.
• The presence of high-avidity autoreactive CD8+ T cells contributes to the pathogenesis of autoimmune diabetes in NOD mice.
• These findings highlight a critical defect in CD8+ T cell self-tolerance that could be a therapeutic target.