Regulatory CD8 T cells that recognize Qa-1 expressed by CD4 T-helper cells inhibit rejection of heart allografts
| Autor: | Amr Mansouri, Siawosh K. Eskandari, Harvey Cantor, John Choi, Jamil Azzi, Melissa Y. Yeung, Eman Alhussain, Saif A. Muhsin, Songjie Cai, Hye-Jung Kim, Hazim Allos, Jean Pierre Assaker, Marc A. Seelen, Ina Sulkaj, Juliano B. Alhaddad |
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| Přispěvatelé: | Groningen Institute for Organ Transplantation (GIOT), Groningen Kidney Center (GKC) |
| Rok vydání: | 2020 |
| Předmět: |
Graft Rejection
DISRUPTION 0301 basic medicine Isoantigens HLA-E Receptors Antigen T-Cell chemical and pharmacologic phenomena Human leukocyte antigen Biology Major histocompatibility complex T-Lymphocytes Regulatory ANTIBODY-MEDIATED REJECTION Mice 03 medical and health sciences 0302 clinical medicine CD8 Treg Ab-mediated rejection Isoantibodies Immune Tolerance Animals Humans Point Mutation Transplantation Homologous Cytotoxic T cell follicular helper T cell Immunologic Tolerance Multidisciplinary Myocardium Qa-1 Graft Survival Histocompatibility Antigens Class I T-cell receptor T-Lymphocytes Helper-Inducer Biological Sciences Allografts Disease Models Animal 030104 developmental biology Immunology biology.protein Heart Transplantation Antibody CD8 030215 immunology |
| Zdroj: | Proc Natl Acad Sci U S A Proceedings of the National Academy of Sciences of the United States of America, 117(11), 6042-6046. NATL ACAD SCIENCES |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1918950117 |
| Popis: | Induction of longstanding immunologic tolerance is essential for survival of transplanted organs and tissues. Despite recent advances in immunosuppression protocols, allograft damage inflicted by antibody specific for donor organs continues to represent a major obstacle to graft survival. Here we report that activation of regulatory CD8 T cells (CD8 Treg) that recognize the Qa-1 class Ib major histocompatibility complex (MHC), a mouse homolog of human leukocyte antigen-E (HLA-E), inhibits antibody-mediated immune rejection of heart allografts. We analyzed this response using a mouse model that harbors a point mutation in the class Ib MHC molecule Qa-1, which disrupts Qa-1 binding to the T cell receptor (TCR)-CD8 complex and impairs the CD8 Treg response. Despite administration of cytotoxic T lymphocyte antigen 4 (CTLA-4) immunoglobulin (Ig), Qa-1 mutant mice developed robust donor-specific antibody responses and accelerated heart graft rejection. We show that these allo-antibody responses reflect diminished Qa-1-restricted CD8 Treg-mediated suppression of host follicular helper T cell-dependent antibody production. These findings underscore the critical contribution of this Qa-1/HLA-E-dependent regulatory pathway to maintenance of transplanted organs and suggest therapeutic approaches to ameliorate allograft rejection. |
| Databáze: | OpenAIRE |
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