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Increased frequency or activity of autoreactive T cells and failures of regulatory T cells (Tregs) to control these pathogenic effectors have both been implicated in T1D etiology. Due to the expression of MHC class I molecules on \u03b2 cells, CD8 T cells represent the ultimate effector population mediating T1D. Developing autoreactive CD8 T cells normally undergo extensive thymic negative selection, but this process is impaired in NOD mice and also likely T1D patients. Previous studies identified an allelic variant of Nfkbid, a NF-\u03baB signal modulator, as a gene strongly contributing to defective thymic deletion of autoreactive CD8 T cells in NOD mice. These previous studies found ablation of Nfkbid in NOD mice using the clustered regularly interspaced short palindromic repeats system resulted in greater thymic deletion of pathogenic CD8 AI4 and NY8.3 TCR transgenic T cells but an unexpected acceleration of T1D onset. This acceleration was associated with reductions in the frequency of peripheral Tregs. In this article, we report transgenic overexpression of Nfkbid in NOD mice also paradoxically results in enhanced thymic deletion of autoreactive CD8 AI4 T cells. However, transgenic elevation of Nfkbid expression also increased the frequency and functional capacity of peripheral Tregs, in part contributing to the induction of complete T1D resistance. Thus, future identification of a pharmaceutical means to enhance Nfkbid expression might ultimately provide an effective T1D intervention approach.<\/jats:p>","DOI":"10.4049\/jimmunol.2100558","type":"journal-article","created":{"date-parts":[[2022,7,14]],"date-time":"2022-07-14T15:14:04Z","timestamp":1657811644000},"page":"227-237","source":"Crossref","is-referenced-by-count":15,"title":["Nfkbid Overexpression in Nonobese Diabetic Mice Elicits Complete Type 1 Diabetes Resistance in Part Associated with Enhanced Thymic Deletion of Pathogenic CD8 T Cells and Increased Numbers and Activity of Regulatory T Cells"],"prefix":"10.1093","volume":"209","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5893-6026","authenticated-orcid":false,"given":"Jennifer R","family":"Dwyer","sequence":"first","affiliation":[{"name":"The Jackson Laboratory , Bar Harbor, ME"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5514-3074","authenticated-orcid":false,"given":"Jeremy J","family":"Racine","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory , Bar Harbor, ME"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harold D","family":"Chapman","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory , Bar Harbor, ME"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8174-5386","authenticated-orcid":false,"given":"Anna","family":"Quinlan","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory , Bar Harbor, ME"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0160-6528","authenticated-orcid":false,"given":"Maximiliano","family":"Presa","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory , Bar Harbor, ME"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5707-8165","authenticated-orcid":false,"given":"Grace A","family":"Stafford","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory , Bar Harbor, ME"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5360-0419","authenticated-orcid":false,"given":"Ingo","family":"Schmitz","sequence":"additional","affiliation":[{"name":"Department of Molecular Immunology, Ruhr-University , Bochum,","place":["Germany"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7614-5925","authenticated-orcid":false,"given":"David V","family":"Serreze","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory , Bar Harbor, ME"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,7,15]]},"reference":[{"key":"2025021008213378200_r1","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/ng.3245","article-title":"Fine mapping of type 1 diabetes susceptibility loci and evidence for colocalization of causal variants with lymphoid gene enhancers","volume":"47","author":"Onengut-Gumuscu","year":"2015","journal-title":"Nat. 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