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 inter...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2014-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC4028311?pdf=render |
| _version_ | 1828879481335447552 |
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| author | Ivana Durinovic-Belló Vivian H Gersuk Chester Ni Rebecca Wu Jerill Thorpe Nicholas Jospe Srinath Sanda Carla J Greenbaum Gerald T Nepom |
| author_facet | Ivana Durinovic-Belló Vivian H Gersuk Chester Ni Rebecca Wu Jerill Thorpe Nicholas Jospe Srinath Sanda Carla J Greenbaum Gerald T Nepom |
| author_sort | Ivana Durinovic-Belló |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T09:29:14Z |
| format | Article |
| id | doaj.art-5c1f3d12ff434afd83a179e2502e4265 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-13T09:29:14Z |
| publishDate | 2014-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-5c1f3d12ff434afd83a179e2502e42652022-12-21T23:52:32ZengPublic Library of Science (PLoS)PLoS ONE1932-62032014-01-0195e9807410.1371/journal.pone.0098074Avidity-dependent programming of autoreactive T cells in T1D.Ivana Durinovic-BellóVivian H GersukChester NiRebecca WuJerill ThorpeNicholas JospeSrinath SandaCarla J GreenbaumGerald T NepomFate 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.http://europepmc.org/articles/PMC4028311?pdf=render |
| spellingShingle | Ivana Durinovic-Belló Vivian H Gersuk Chester Ni Rebecca Wu Jerill Thorpe Nicholas Jospe Srinath Sanda Carla J Greenbaum Gerald T Nepom Avidity-dependent programming of autoreactive T cells in T1D. PLoS ONE |
| title | Avidity-dependent programming of autoreactive T cells in T1D. |
| title_full | Avidity-dependent programming of autoreactive T cells in T1D. |
| title_fullStr | Avidity-dependent programming of autoreactive T cells in T1D. |
| title_full_unstemmed | Avidity-dependent programming of autoreactive T cells in T1D. |
| title_short | Avidity-dependent programming of autoreactive T cells in T1D. |
| title_sort | avidity dependent programming of autoreactive t cells in t1d |
| url | http://europepmc.org/articles/PMC4028311?pdf=render |
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