Avidity-dependent programming of autoreactive T cells in T1D.
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.
Benaroya Research Institute at Virginia Mason, Seattle, Washington, United States of America.
Ivana
I
Durinovic-Belló
Benaroya Research Institute at Virginia Mason, Seattle, Washington, United States of America.
Vivian H
VH
Gersuk
Benaroya Research Institute at Virginia Mason, Seattle, Washington, United States of America.
Chester
C
Ni
Benaroya Research Institute at Virginia Mason, Seattle, Washington, United States of America.
Rebecca
R
Wu
Benaroya Research Institute at Virginia Mason, Seattle, Washington, United States of America.
Jerill
J
Thorpe
University of Rochester School of Medicine, Rochester, New York, United States of America.
Nicholas
N
Jospe
Benaroya Research Institute at Virginia Mason, Seattle, Washington, United States of America.
Srinath
S
Sanda
Benaroya Research Institute at Virginia Mason, Seattle, Washington, United States of America.
Carla J
CJ
Greenbaum
Benaroya Research Institute at Virginia Mason, Seattle, Washington, United States of America; University of Washington School of Medicine, Seattle, Washington, United States of America.
Gerald T
GT
Nepom
D000328:Adult; D001324:Autoantigens / Q000276:immunology; D015551:Autoimmunity; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D005260:Female; D020869:Gene Expression Profiling; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000235:genetics / Q000276:immunology; D008297:Male; D008875:Middle Aged; D011384:Proinsulin / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011485:Protein Binding; D011948:Receptors, Antigen, T-Cell; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D055815:Young Adult
D001324:Autoantigens; D007328:Insulin; D011948:Receptors, Antigen, T-Cell; D011384:Proinsulin