Our aim is to understand how the autoimmunity against pancreatic β cells develops and progresses toward type 1 diabetes (T1D), and how to halt this progression, before β-cell destruction and clinical disease. β-cell destruction involves the recognition of peptide-HLA Class I (pHLA-I) complexes on the surface of β cells by autoreactive CD8+ T cells. Surprisingly, we observed that CD8+ T cells recognizing known and novel β-cell peptides, that we identified by HLA peptidomics and transcriptomics strategies, circulate at a similar frequency in T1D and healthy donors and display a largely naïve phenotype (Culina et al. Sci Immunol 2018, Gonzalez-Duque et al. Cell Metab 2018, Azoury et al. Diabetes 2020). Thus, a universal state of ‘benign’ islet autoimmunity exists in all individuals, to a much larger extent than previously appreciated.

The overall objective of our Laboratory is to decipher the mechanisms by which this benign autoimmunity progresses toward T1D in few individuals, and not in many others. We propose that such progression may rely on two non-mutually exclusive mechanisms: a) loss of immune ignorance toward β-cell antigens that are normally invisible to T cells (β-cell-centric hypothesis); and b) loss of the immune regulation that controls autoreactive T cells (T-cell-centric hypothesis).

We are investigating whether progression to T1D involves a different vulnerability of β cells in the face of a naïve autoimmune repertoire that is similar across individuals. This vulnerability may be modulated by a different pHLA presentation by β cells or dendritic cells (DCs) in the T1D and healthy conditions. In this context, we are studying:

  1. the peptide antigen display of β cells under resting versus inflammatory conditions, or upon infection by Enteroviruses (which are the most credited environmental triggers for T1D).
  2. the role of other surface molecules that may further modulate this vulnerability.