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

• Published in: Immunity (Cambridge, Mass.) Mass.), 2019-01, Vol.50 (1), p.152-165.e8
• Main Authors: Jayachandran, Rajesh, Gumienny, Aleksandra, Bolinger, Beatrice, Ruehl, Sebastian, Lang, Mathias Jakob, Fucile, Geoffrey, Mazumder, Saumyabrata, Tchang, Vincent, Woischnig, Anne-Kathrin, Stiess, Michael, Kunz, Gabriele, Claudi, Beatrice, Schmaler, Mathias, Siegmund, Kerstin, Li, Jianping, Dertschnig, Simone, Holländer, George, Medina, Eva, Karrer, Urs, Moshous, Despina, Bumann, Dirk, Khanna, Nina, Rossi, Simona W., Pieters, Jean
• Format: Article
• Language: English
• Subjects: Adenosine monophosphate; Allografts; Antigen-presenting cells; Antigens; Cyclic AMP; Disruption; Gene expression; Graft rejection; Homeostasis; Immune system; Immunity; Immunological tolerance; Immunosuppression; Infections; Kinases; Lymphocytes; Lymphocytes T; Microorganisms; Modulation; Ontology; Pathogens; Peptides; Pharmacology; Proteins; Rejection; Spleen; Survival analysis; T cell receptors; Transplants & implants
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2018.12.011

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. [Display omitted] •Mice lacking coronin 1 show tolerance toward allografts•Costimulation from infected APCs breaks the tolerance to clear pathogens•Coronin 1-deficiency affects CAMKIV-mediated CREB activation in T cells•Prior transfer of coronin 1-deficient T cells promote tolerance toward allografts Avoiding infection as a consequence of immunosuppression following organ transplantation has been elusive. Here, Jayachandran et al. demonstrate that targeting the immunoregulatory protein coronin 1 in mice results in allograft-specific tolerance in the absence of immunosuppression-associated co-morbidities. Coronin 1-deficiency increased cAMP concentrations to suppress allo-specific T cell responses without compromising pathogen-specific immunity and may represent an attractive therapeutic target.