T cell promiscuity in autoimmune diabetes

Abstract

Objective: It is well established that the primary mediators of β cell destruction in type 1 diabetes are T cells. Nevertheless, the molecular basis for recognition of β cell-specific epitopes by pathogenic T cells remains ill-defined.

Research Design and Methods: To determine the properties of β cell-specific T cell receptors (TCRs), we characterized the fine specificity, functional and relative binding avidity/affinity and diabetogenicity of a panel of GAD65-specific CD4⁺ T cell clones established from unimmunized 4 and 14 week-old NOD female mice.

Results: The majority of GAD65-specific CD4⁺ T cells isolated from 4 and 14-week-old NOD female mice were specific for peptides spanning amino acids 217-236 (p217) and 290-309 (p290). Surprisingly, 31% of the T cell clones prepared from 14 week-old but not younger NOD mice were stimulated with both p217 and p290. These promiscuous T cell clones recognized the two epitopes when naturally processed and presented, and this dual specificity was mediated by a single TCR. Furthermore, promiscuous T cell clones demonstrated increased functional avidity and relative TCR binding affinity, which correlated with enhanced islet infiltration upon adoptive transfer compared to mono-specific T cell clones.

Conclusions: These results indicate that promiscuous recognition contributes to the development of GAD65-specific CD4⁺ T cell clones in NOD mice. Furthermore, these findings suggest that T cell promiscuity reflects a novel form of T cell avidity maturation.