Hypoimmunogenic HLA-E Single Chain Inhibits Alloreactive Immune Responses.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: American Association of Immunologists Country of Publication: United States NLM ID: 2985117R Publication Model: Print Cited Medium: Internet ISSN: 1550-6606 (Electronic) Linking ISSN: 00221767 NLM ISO Abbreviation: J Immunol Subsets: MEDLINE
    • Publication Information:
      Publication: Bethesda, MD : American Association of Immunologists
      Original Publication: Baltimore : Williams & Wilkins, c1950-
    • Subject Terms:
      Histocompatibility Antigens Class I*/immunology ; HLA-E Antigens* ; Killer Cells, Natural*/immunology ; CD8-Positive T-Lymphocytes*/immunology; Humans ; Lymphocyte Activation/immunology ; Receptors, Chimeric Antigen/immunology ; Receptors, Chimeric Antigen/genetics ; Immune Tolerance/immunology
    • 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 β2-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 α3 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.
      (Copyright © 2024 by The American Association of Immunologists, Inc.)
    • Accession Number:
      0 (Histocompatibility Antigens Class I)
      0 (HLA-E Antigens)
      0 (Receptors, Chimeric Antigen)
    • Publication Date:
      Date Created: 20241202 Date Completed: 20241202 Latest Revision: 20241202
    • Publication Date:
      20241204
    • Accession Number:
      10.4049/jimmunol.2400491
    • Accession Number:
      39621955