To study Treg suppression in inflamed non-lymphoid tissues, Dai et al. used time-lapse intravital microscopy in an inflammatory allogeneic islet transplantation model to visualize dynamics and mechanisms of CD4+Foxp3+ Treg suppression of tumor rejection by effector T cells (Teff). Tregs were highly motile,migrated to inflamed islets, did not require priming, and preferred contacts with CD11+ APC simultaneously in contact with Teff that resulted in decreased MHC-II expression on APCs and IFNγ in Teff. Treg suppressor function required ecto-nucleotidase CD73, as CD73-/- Tregs exhibited reduced contacts with APCs in inflamed allografts compared to wild-type Treg.
Contributed by Katherine Turner
ABSTRACT: Regulatory CD4+Foxp3+ T cells (Treg) restrain inflammation and immunity. However, the mechanisms underlying Treg suppressor function in inflamed non-lymphoid tissues remain largely unexplored. Here, we restricted immune responses to non-lymphoid tissues and used intravital microscopy to visualize Treg suppression of rejection by effector T cells (Teff) within inflamed allogeneic islet transplants. Despite their elevated motility, Treg preferentially contact antigen-presenting cells (APCs) over Teff. Interestingly, Treg specifically target APCs that are extensively and simultaneously contacted by Teff. In turn, Treg decrease MHC-II expression on APCs and hinder Teff function. Lastly, we demonstrate that Treg suppressor function within inflamed allografts requires ecto-nucleotidase CD73 activity, which generates the anti-inflammatory adenosine. Consequently, CD73-/- Treg exhibit reduced contacts with APCs within inflamed allografts compared to wt Treg, but not in spleen. Overall, our findings demonstrate that Treg suppress immunity within inflamed grafts through CD73 activity and suggest that Treg-APC direct contacts are central to this process.
Author Info: (1) Departments of Surgery and Immunology, Thomas E. Starzl Transplantation Institute- University of Pittsburgh, Pittsburgh, United States of America. (2) Departments of Surgery an
Author Info: (1) Departments of Surgery and Immunology, Thomas E. Starzl Transplantation Institute- University of Pittsburgh, Pittsburgh, United States of America. (2) Departments of Surgery and Immunology, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, United States of America. (3) Departments of Surgery and Immunology, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, United States of America. (4) Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America. (5) Department of Cell Biology and Physiology, University of Pittsburgh School of Medicine, Pittsburgh, United States of America. (6) Departments of Surgery and Immunology, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, United States of America.
