GAD65-Specific CD4+ T-Cells with High Antigen Avidity Are Prevalent in Peripheral Blood of Patients With Type 1 Diabetes

  1. Helena Reijonen,
  2. Roberto Mallone,
  3. Anne-Kristin Heninger,
  4. Elsa M. Laughlin,
  5. Sharon A. Kochik,
  6. Ben Falk,
  7. William W. Kwok,
  8. Carla Greenbaum and
  9. Gerald T. Nepom
  1. From the Benaroya Research Institute at Virginia Mason, Seattle, Washington
  1. Address correspondence and reprint requests to Helena Reijonen, Benaroya Research Institute at Virginia Mason, 1201 9th Avenue, Seattle, WA 98101. E-mail: reijonen{at}benaroyaresearch.org

Abstract

Negative selection of self-reactive T-cells during thymic development, along with activation-induced cell death in peripheral lymphocytes, is designed to limit the expansion and persistence of autoreactive T-cells. Autoreactive T-cells are nevertheless present, both in patients with type 1 diabetes and in at-risk subjects. By using MHC class II tetramers to probe the T-cell receptor (TcR) specificity and avidity of GAD65 reactive T-cell clones isolated from patients with type 1 diabetes, we identified high-avidity CD4+ T-cells in peripheral blood, coexisting with low-avidity cells directed to the same GAD65 epitope specificity. A variety of cytokine patterns was observed, even among T-cells with high MHC-peptide avidity, and the clones utilize a biased set of TcR genes that favor two combinations, Vα12-β5.1 and Vα17-Vβ4. Presence of these high-avidity TcRs indicates a failure to delete autoreactive T-cells that likely arise from oligoclonal expansion in response to autoantigen exposure during the progression of type 1 diabetes.

Footnotes

    • Accepted April 29, 2004.
    • Received November 7, 2003.
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