{"id":19797,"date":"2024-12-03T00:49:12","date_gmt":"2024-12-02T23:49:12","guid":{"rendered":"https:\/\/inmuno.es\/index.php\/2024\/12\/03\/hypoimmunogenic-hla-e-single-chain-inhibits-alloreactive-immune-responses\/"},"modified":"2024-12-03T00:49:12","modified_gmt":"2024-12-02T23:49:12","slug":"hypoimmunogenic-hla-e-single-chain-inhibits-alloreactive-immune-responses","status":"publish","type":"post","link":"https:\/\/inmuno.es\/index.php\/2024\/12\/03\/hypoimmunogenic-hla-e-single-chain-inhibits-alloreactive-immune-responses\/","title":{"rendered":"Hypoimmunogenic HLA-E Single Chain Inhibits Alloreactive Immune Responses"},"content":{"rendered":"<div>\n<p>J Immunol. 2024 Dec 15;213(12):1799-1810. doi: 10.4049\/jimmunol.2400491.<\/p>\n<p>ABSTRACT<\/p>\n<p>Chimeric Ag receptor T cells derived from universal donors are susceptible to recipient immunologic rejection, which may limit their in vivo persistence and compromise treatment efficacy. In this study, we generated HLA class I-deficient T cells by disrupting \u03b22-microglobulin to evade recognition by HLA-mismatched CD8+ T cells, and then restored NK cell tolerance by forced expression of an HLA-E single-chain receptor. We specifically report on an optimized hypoimmunogenic disulfide trap HLA-E4 (dtHLA-E4) molecule that exhibited increased surface expression, enhanced NK cell inhibitory potential, and abrogated CD8-dependent T cell recognition. Our dtHLA-E4 molecule comprised the CD4 (4) transmembrane domain and truncated cytoplasmic region, as well as disulfide trap mutations to anchor an HLA class I signal sequence-derived peptide. Functional comparison of dtHLA-E4 molecules fused to different VL9 epitopes showed that peptides derived from HLA-A and HLA-C allotypes maximized NK cell inhibition and minimized NKG2C+ NK cell activation. Furthermore, incorporation of mutations into the \u03b13 domain of HLA-E diminished the immunogenicity of dtHLA-E4 by reducing CD8+ T cell recognition, but crucially, these mutations left NK cell inhibitory function intact. These findings demonstrate the systematic construction of a hypoimmunogenic dtHLA-E4 molecule, which promises to facilitate persistence of allogeneic HLA class I-deficient chimeric Ag receptor T cells by overcoming NK cell missing-self recognition.<\/p>\n<p>PMID:<a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/39621955\/?utm_source=WordPress&amp;utm_medium=rss&amp;utm_content=2985117R&amp;ff=20241202184911&amp;v=2.18.0.post9+e462414\">39621955<\/a> | DOI:<a href=\"https:\/\/doi.org\/10.4049\/jimmunol.2400491\">10.4049\/jimmunol.2400491<\/a><\/p>\n<\/div>","protected":false},"excerpt":{"rendered":"<p>J Immunol. 2024 Dec 15;213(12):1799-1810. doi: 10.4049\/jimmunol.2400491. ABSTRACT Chimeric Ag receptor T cells derived from universal donors are susceptible to recipient immunologic rejection, which may limit their in vivo persistence and compromise treatment efficacy. In this study, we generated HLA class I-deficient T cells by disrupting \u03b22-microglobulin to evade recognition by HLA-mismatched CD8+ T cells, &#8230; <a title=\"Hypoimmunogenic HLA-E Single Chain Inhibits Alloreactive Immune Responses\" class=\"read-more\" href=\"https:\/\/inmuno.es\/index.php\/2024\/12\/03\/hypoimmunogenic-hla-e-single-chain-inhibits-alloreactive-immune-responses\/\" aria-label=\"Read more about Hypoimmunogenic HLA-E Single Chain Inhibits Alloreactive Immune Responses\">Read more<\/a><\/p>\n","protected":false},"author":0,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[42,71],"tags":[],"class_list":["post-19797","post","type-post","status-publish","format-standard","hentry","category-publicaciones","category-the-journal-of-immunology"],"_links":{"self":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/19797","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/types\/post"}],"replies":[{"embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/comments?post=19797"}],"version-history":[{"count":0,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/posts\/19797\/revisions"}],"wp:attachment":[{"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/media?parent=19797"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/categories?post=19797"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/inmuno.es\/index.php\/wp-json\/wp\/v2\/tags?post=19797"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}