Disruption of Coronin 1 Signaling in T Cells Promotes Allograft Tolerance while Maintaining Anti-Pathogen Immunity

Immunity. 2019 Jan 15;50(1):152-165.e8. doi: 10.1016/j.immuni.2018.12.011. Epub 2019 Jan 2.

Abstract

The ability of the immune system to discriminate self from non-self is essential for eradicating microbial pathogens but is also responsible for allograft rejection. Whether it is possible to selectively suppress alloresponses while maintaining anti-pathogen immunity remains unknown. We found that mice deficient in coronin 1, a regulator of naive T cell homeostasis, fully retained allografts while maintaining T cell-specific responses against microbial pathogens. Mechanistically, coronin 1-deficiency increased cyclic adenosine monophosphate (cAMP) concentrations to suppress allo-specific T cell responses. Costimulation induced on microbe-infected antigen presenting cells was able to overcome cAMP-mediated immunosuppression to maintain anti-pathogen immunity. In vivo pharmacological modulation of this pathway or a prior transfer of coronin 1-deficient T cells actively suppressed allograft rejection. These results define a coronin 1-dependent regulatory axis in T cells important for allograft rejection and suggest that modulation of this pathway may be a promising approach to achieve long-term acceptance of mismatched allografts.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allografts / immunology
  • Animals
  • Antigens, Bacterial / immunology
  • Antigens, Fungal / immunology
  • Antigens, Viral / immunology
  • Cells, Cultured
  • Cyclic AMP / immunology
  • Graft Rejection / immunology*
  • Graft Survival
  • Heart Transplantation*
  • Homeostasis / genetics
  • Humans
  • Immunity
  • Immunosuppression
  • Infections / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Microfilament Proteins / metabolism*
  • Signal Transduction
  • Skin Transplantation*
  • T-Lymphocytes / immunology*
  • Transplantation Tolerance

Substances

  • Antigens, Bacterial
  • Antigens, Fungal
  • Antigens, Viral
  • Microfilament Proteins
  • coronin proteins
  • Cyclic AMP