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

Research output: Contribution to journalArticle

Authors

  • 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

External Institution(s)

  • Harvard University
  • University of Groningen
  • Dana-Farber Cancer Institute

Details

Original languageEnglish (US)
Pages (from-to)6042-6046
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume117
Issue number11
StatusPublished - Mar 17 2020
Peer-reviewedYes

Abstract

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.

    Research areas

  • Ab-mediated rejection, CD8 Treg, Follicular helper T cell, HLA-E, Qa-1

Citation formats

APA

Choi, J. Y., Eskandari, S. K., Cai, S., Sulkaj, I., Assaker, J. P., Allos, H., ... Azzi, J. R. (2020). Regulatory CD8 T cells that recognize Qa-1 expressed by CD4 T-helper cells inhibit rejection of heart allografts. Proceedings of the National Academy of Sciences of the United States of America, 117(11), 6042-6046. https://doi.org/10.1073/pnas.1918950117

Harvard

Choi, JY, Eskandari, SK, Cai, S, Sulkaj, I, Assaker, JP, Allos, H, AlHaddad, J, Muhsin, SA, Alhussain, E, Mansouri, A, Yeung, MY, Seelen, MAJ, Kim, HJ, Cantor, H & Azzi, JR 2020, 'Regulatory CD8 T cells that recognize Qa-1 expressed by CD4 T-helper cells inhibit rejection of heart allografts', Proceedings of the National Academy of Sciences of the United States of America, vol. 117, no. 11, pp. 6042-6046. https://doi.org/10.1073/pnas.1918950117