The Frequency and Immunodominance of Islet-specific CD8⁺ T-cell Responses Change after Type 1 Diabetes Diagnosis and Treatment

Abstract

Objective: Islet-reactive CD8⁺ T-cells play a key role in the pathogenesis of type 1 diabetes (T1D) in the NOD mouse. The predominant T-cell specificities change over time, but whether similar shifts also occur after clinical diagnosis and insulin treatment in T1D patients is unknown.

Research Design And Methods: We took advantage of a recently validated islet-specific CD8⁺ T-cell IFN-γ enzyme-linked immunospot (ISL8Spot) assay to follow responses against preproinsulin (PPI), GAD, IA-2 and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) epitopes in 15 HLA-A2⁺ adult T1D patients close to diagnosis and at a second time point 7-16 months after.

Results: CD8⁺ T-cell reactivities were less frequent at follow-up, as 28.6% of responses tested positive at T1D diagnosis vs. 13.2% after a median of 11 months (P=0.003). While GAD and IA-2 autoantibody (aAb) titers were unchanged in 75% of cases, the fraction of patients responding to PPI and/or GAD epitopes by ISL8Spot decreased from 60-67% to 20% (P<0.02). The previously subdominant IA-2_206-214 and IGRP_265-273 peptides were newly targeted, thus becoming the immunodominant epitopes.

Conclusions: Shifts both in frequency and in immunodominance of CD8⁺ T-cell responses occur rapidly, as compared to slower changes in aAb titers. These different kinetics may suggest complementary clinical applications for T cell and aAb measurements.