Failure to censor forbidden clones of CD4 T cells in autoimmune diabetes

Sylvie Lesage, Suzanne B. Hartley, Srinivas Akkaraju, Judith Wilson, Michelle Townsend, Christopher C. Goodnow*

*Corresponding author for this work

    Research output: Contribution to journalArticlepeer-review

    131 Citations (Scopus)

    Abstract

    Type 1 diabetes and other organ-specific autoimmune diseases often cluster together in human families and in congenic strains of NOD (nonobese diabetic) mice, but the inherited immuno-regulatory defects responsible for these diseases are unknown. Here we track the fate of high avidity CD4 T cells recognizing a self-antigen expressed in pancreatic islet β cells using a transgenic mouse model. T cells of identical specificity, recognizing a dominant peptide from the same islet antigen and major histocompatibility complex (MHC)-presenting molecule, were followed on autoimmune susceptible and resistant genetic backgrounds. We show that non-MHC genes from the NOD strain cause a failure to delete these high avidity autoreactive T cells during their development in the thymus, with subsequent spontaneous breakdown of CD4 cell tolerance to the islet antigen, formation of intra-islet germinal centers, and high titre immunoglobulin G1 autoantibody production. In mixed bone marrow chimeric animals, defective thymic deletion was intrinsic to T cells carrying diabetes susceptibility genes. These results demonstrate a primary failure to censor forbidden clones of self-reactive T cells in inherited susceptibility to organ-specific autoimmune disease, and highlight the importance of thymic mechanisms of tolerance in organ-specific tolerance.

    Original languageEnglish
    Pages (from-to)1175-1188
    Number of pages14
    JournalJournal of Experimental Medicine
    Volume196
    Issue number9
    DOIs
    Publication statusPublished - 4 Nov 2002

    Fingerprint

    Dive into the research topics of 'Failure to censor forbidden clones of CD4 T cells in autoimmune diabetes'. Together they form a unique fingerprint.

    Cite this