Poster Presentation The 13th International Congress of the Immunology of Diabetes Society 2013

Avidity-dependent programing of autoreactive T cells in type 1 diabetes (#76)

Ivana Durinovic-Bello 1 , Vivian H Gersuk 1 , Chester Ni 1 , Rebeca Wu 1 , Jerill Thorpe 1 , Nicholas Jospe 2 , Carla J Greenbaum 1 , Gerald T Nepom 1
  1. Benaroya Research Institute at Virginia Mason, Seattle, WA, United States
  2. Department of Pediatrics, University of Rochester, Rochester, NY, United States
Fate determination for autoreactive T cells relies on a series of avidity-dependent interactions during T cell selection, represented by two general types of signals, one based on antigen expression and density during T cell development, and one based on genes that interpret the avidity of TCR interaction to guide developmental outcome. We used proinsulin-specific HLA class II tetramers to purify and determine transcriptional signatures for autoreactive T cells under differential selection in type 1 diabetes (T1D), in which insulin (INS) genotypes consist of protective and susceptible alleles that regulate the level of proinsulin expression in the thymus. Upregulation of steroid nuclear receptor family 4A (NR4A) and early growth response family genes in proinsulin-specific T cells with susceptible INS-VNTR genotypes suggests a mechanism for avidity-dependent fate determination of the T cell repertoire in T1D. The NR4A genes act as translators of TCR signal strength that guide central and peripheral T cell fate decisions through transcriptional modification. We propose that autoreactive T cells in T1D reflect their prior developmental experience influenced by proinsulin expression under genetic control and by maintenance of an NR4A-guided program in low avidity T cells that escape negative selection.