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Extraction of Tissue Antigens for Functional Assays
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Characterizing T cell responses to enzymatically modified beta cell neo-epitopes.

Hai Nguyen1, David Arribas-Layton1, I-Ting Chow1

  • 1Center for Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, WA, United States.

Frontiers in Immunology
|January 27, 2023
PubMed
Summary

T cells recognizing modified self-peptides are more common in type 1 diabetes (T1D). Specific T cell responses to neo-antigens correlate with faster loss of beta cell function in T1D patients.

Keywords:
T cellType 1 diabetes (T1D)at riskcitrullinated autoantigensdeamidated autoantigens

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Area of Science:

  • Immunology
  • Endocrinology
  • Autoimmunity

Background:

  • Post-translationally modified (PTM) self-peptides are recognized by T cells in type 1 diabetes (T1D).
  • The prevalence, function, and disease correlation of T cells recognizing different PTM self-peptides remain unclear.

Purpose of the Study:

  • To investigate the frequency and functional phenotypes of T cells recognizing PTM GAD and PTM IA2 epitopes in T1D subjects.
  • To determine if T cell responses correlate with residual beta cell function and disease progression.

Main Methods:

  • Identified a cohort of T1D subjects with varying residual beta cell function.
  • Used HLA class II tetramer reagents to enumerate T cells recognizing PTM GAD and PTM IA2 epitopes.
  • Analyzed T cell functional phenotypes (cytokine production, surface markers) and correlated with clinical data.

Main Results:

  • T cells recognizing PTM GAD and PTM IA2 epitopes were found at higher frequencies in T1D subjects compared to controls.
  • GAD-specific T cells were more numerous than IA2-specific T cells in T1D.
  • Neo-epitope specific T cells exhibited a predominantly Th1-like phenotype, with some poly-functional cells.
  • Responses to PTM IA2 were linked to lower residual beta cell function.
  • At-risk subjects showed neo-epitope specific T cells, with higher IFN-γ/IL-4 ratios in those with multiple autoantibodies.

Conclusions:

  • PTM neo-epitopes are relevant in T1D pathogenesis.
  • Distinct neo-antigen responses may accelerate beta cell function decline in T1D.