Clonal copy-number mosaicism in autoreactive T lymphocytes in diabetic NOD mice

Genome Res. 2019 Dec;29(12):1951-1961. doi: 10.1101/gr.247882.118. Epub 2019 Nov 6.

Abstract

Concordance for type 1 diabetes (T1D) is far from 100% in monozygotic twins and in inbred nonobese diabetic (NOD) mice, despite genetic identity and shared environment during incidence peak years. This points to stochastic determinants, such as postzygotic mutations (PZMs) in the expanding antigen-specific autoreactive T cell lineages, by analogy to their role in the expanding tumor lineage in cancer. Using comparative genomic hybridization of DNA from pancreatic lymph-node memory CD4+ T cells of 25 diabetic NOD mice, we found lymphocyte-exclusive mosaic somatic copy-number aberrations (CNAs) with highly nonrandom independent involvement of the same gene(s) across different mice, some with an autoimmunity association (e.g., Ilf3 and Dgka). We confirmed genes of interest using the gold standard approach for CNA quantification, multiplex ligation-dependent probe amplification (MLPA), as an independent method. As controls, we examined lymphocytes expanded during normal host defense (17 NOD and BALB/c mice infected with Leishmania major parasite). Here, CNAs found were fewer and significantly smaller compared to those in autoreactive cells (P = 0.0019). We determined a low T cell clonality for our samples suggesting a prethymic formation of these CNAs. In this study, we describe a novel, unexplored phenomenon of a potential causal contribution of PZMs in autoreactive T cells in T1D pathogenesis. We expect that exploration of point mutations and studies in human T cells will enable the further delineation of driver genes to target for functional studies. Our findings challenge the classical notions of autoimmunity and open conceptual avenues toward individualized prevention and therapeutics.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes* / immunology
  • CD4-Positive T-Lymphocytes* / pathology
  • Diabetes Mellitus, Type 1* / genetics
  • Diabetes Mellitus, Type 1* / immunology
  • Diabetes Mellitus, Type 1* / pathology
  • Gene Dosage*
  • Genome-Wide Association Study
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred NOD
  • Mosaicism*
  • Mutation*
  • Point Mutation*