Regulatory CD8 T cells that recognize Qa-1 expressed by CD4 T-helper cells inhibit rejection of heart allografts

John Y. Choi, Siawosh K. Eskandari, Songjie Cai, Ina Sulkaj, Jean Pierre Assaker, Hazim Allos, Juliano AlHaddad, Saif A. Muhsin, Eman Alhussain, Amr Mansouri, Melissa Y. Yeung, Marc A. J. Seelen, Hye-Jung Kim, Harvey Cantor*, Jamil R. Azzi

*Corresponding author voor dit werk

OnderzoeksoutputAcademicpeer review

21 Citaten (Scopus)
86 Downloads (Pure)

Samenvatting

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.

Originele taal-2English
Pagina's (van-tot)6042-6046
Aantal pagina's5
TijdschriftProceedings of the National Academy of Sciences of the United States of America
Volume117
Nummer van het tijdschrift11
DOI's
StatusPublished - 17-mrt.-2020

Vingerafdruk

Duik in de onderzoeksthema's van 'Regulatory CD8 T cells that recognize Qa-1 expressed by CD4 T-helper cells inhibit rejection of heart allografts'. Samen vormen ze een unieke vingerafdruk.

Citeer dit