Disruption of Coronin 1 Signaling in T Cells Promotes Allograft Tolerance while Maintaining Anti-Pathogen Immunity.
Jayachandran, Rajesh 1,*; Gumienny, Aleksandra 1; Bolinger, Beatrice 1; Ruehl, Sebastian 1; Lang, Mathias Jakob 1; Fucile, Geoffrey 4; Mazumder, Saumyabrata 1; Tchang, Vincent 1; Woischnig, Anne-Kathrin 2; Stiess, Michael 1; Kunz, Gabriele 1; Claudi, Beatrice 1; Schmaler, Mathias 2; Siegmund, Kerstin 1,10; Li, Jianping 5; Dertschnig, Simone 2; Hollander, George 2,6; Medina, Eva 7; Karrer, Urs 8; Moshous, Despina 9; Bumann, Dirk 1; Khanna, Nina 2,3; Rossi, Simona W. 2; Pieters, Jean 1,11,*
[Article]
Immunity.
50(1):152-165,165e1-165e8, January 15, 2019.
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Summary: 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.
* 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
(C) 2019Elsevier, Inc.
