ENVIRONMENTAL PRESSURE ON A DEFECTIVE IMMUNE SELF IMAGE: TOWARDS TYPE 1 DIABETES PREDICTION AND PREVENTION – TIBET

BACKGROUND: The incidence of autoimmune type 1 diabetes (T1D) is steadily increasing in Western countries (4% annual increase in France), affecting children of younger age and imposing a growing toll in terms of quality of life, long-term complications and public heath expenditure. Its environmental triggers remain elusive and tolerogenic vaccination strategies stand unsuccessful, thus precluding disease prevention. Autoreactive T cells play the central pathogenic role in T1D, with CD8+ T cells driving beta-cell destruction through recognition of target antigens (Ags) presented by HLA Class I molecules on the beta-cell surface.

HYPOTHESIS: Failures at three checkpoints in A) thymic Ag presentation, leading to autoreactive T-cell escape; B) environmental exposure, leading to T-cell cross-reactivity; and C) presentation of islet-specific neo-Ags normally ignored by the immune system ignite beta-cell autoimmunity.

SPECIFIC AIMS:
1) To identify and characterize CD8+ T cells recognizing novel neo-Ags generated by mRNA alternative splicing that are islet-specific, upregulated by inflammation, not expressed in the thymus and homologous to microbial sequences. To develop novel molecular assays to track autoimmune T cells based on the detection of their associated T-cell receptors.
2) To define the mechanisms favoring the emergence of these autoreactive T cells: thymic Ag expression patterns, microbial cross-reactivity and inflammation-induced neo-Ag upregulation.
3) To validate a novel neonatal oral vaccination strategy that ‘upgrades’ defective thymic Ag presentation.

RELEVANCE: this research may offer novel T-cell biomarkers to follow progression of islet autoimmunity and to unveil pathogenic mechanisms amenable to therapeutic correction through alternative splicing modulation, correction of incomplete thymic tolerance by neonatal vaccination and identification of candidate environmental triggers to be further validated.