Abstract
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 was observed in individuals with susceptible INS-VNTR genotypes, suggesting 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 maintenance of an NR4A-guided program in low avidity autoreactive T cells in T1D reflects their prior developmental experience influenced by proinsulin expression, identifying a pathway permissive for autoimmunity.
Highlights
Insulin is an important autoantigen in type 1 diabetes (T1D) autoimmunity, most likely the primary causative antigen in the spontaneously diabetic NOD mouse, and a target autoantigen in Caucasian individuals with the highest HLA-DRB1*04, DQ8 riskhaplotype [1,2,3]
Polymorphisms at the proinsulin locus correlate with genetic susceptibility and with the frequency of proinsulin-specific T cells in the periphery; the insulin (INS) variable number tandem repeat (VNTR) class III (141–209 repeats of a 14base pair-long consensus motif) correlates with a 3-4-fold higher expression level for proinsulin in the thymus and is associated with protection from T1D, whereas INS VNTR class I alleles (26–63 repeats) in homozygous form are associated with lower levels of INS expression in thymus, higher levels in beta cells, and an increased relative risk for T1D that ranges between 1.9–5 [5,6]
We have previously shown that the frequency of proinsulin-specific CD4 T cells in peripheral blood of T1D subjects and healthy controls is higher in DRB1*04:01 subjects homozygous for INS VNTR class I as compared with DRB1*04:01 T1D and healthy controls with INS VNTR class III [7], consistent with a mechanism for the protective effect of the class III alleles, involving more efficient deletion of INS-autoreactive T cells, a process known to be antigen dose dependent [8,9]
Summary
Insulin is an important autoantigen in type 1 diabetes (T1D) autoimmunity, most likely the primary causative antigen in the spontaneously diabetic NOD mouse, and a target autoantigen in Caucasian individuals with the highest HLA-DRB1*04, DQ8 riskhaplotype [1,2,3]. Using HLA class II tetramers for proinsulin epitopes presented by HLA-DR4 molecules, we purified antigen-specific autoreactive CD4 T cells from both control and T1D HLADRB1*04:01 subjects with different INS VNTR genotypes, and compared transcriptional profiles for NR4A and related gene families. T cells from both control and T1D subjects with the T1D-susceptible, INS VNTR I genotype expressed high levels of NR4A family members, linking disease susceptibility with a key homeostatic pathway for T cell regulation. This effect was most pronounced in a subpopulation of T cells with intermediate avidity for the proinsulin epitope, positioning this mechanism at a stage distinct from negative selection of high avidity cells
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