LAUSR

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. Graphical Abstract Figure. No Caption available. HighlightsMice lacking coronin 1 show tolerance toward allograftsCostimulation from infected APCs breaks the tolerance to clear pathogensCoronin 1‐deficiency affects CAMKIV‐mediated CREB activation in T cellsPrior transfer of coronin 1‐deficient T cells promote tolerance toward allografts &NA; 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.