Embryonic stem cell‐derived haematopoietic progenitor cells down‐regulate the CD 3 ξ chain on T cells, abrogating alloreactive T cells

Summary Murine embryonic stem ( ES ) cell‐derived haematopoietic progenitor cells ( HPC s) engraft and populate lymphoid organs. In vivo , HPC s engraft across MHC barriers protecting donor‐type allografts from rejection. However, the underlying phenomenon remains elusive. Here, we sought to determine the mechanism by which ES cell‐derived HPC s regulate alloreactive T cells. We used the 2C mouse, which expresses a transgenic T ‐cell receptor against H2‐L d to determine whether HPC s are deleted by cytotoxic T lymphocytes ( CTL s). Previously, we reported that HPC s express MHC class I antigens poorly and do not express class II antigens. In vitro stimulated 2C CTL s failed to lyse H2‐L d HPC s in a standard 4‐hr 51 chromium release assay. Similarly, when the HPC s were tested in an ELISPOT assay measuring the release of interferon‐ γ by CTL s, HPC s failed to induce CTL degranulation. In addition, mice that were injected with HPC s showed a marked decrease in T ‐cell responses to alloantigen and CD 3 stimulation, but showed a normal response to PMA /ionomycin, suggesting that HPC s impaired T‐cell signalling through the T ‐cell receptor/ CD 3 complex. Here, we show that HPC s secrete arginase, an enzyme that scavenges l ‐arginine, leading to metabolites that down‐regulate CD 3 ζ chain. Indeed an arginase inhibitor partially restored expression of the CD 3 ζ chain, implicating arginase 1 in the down‐regulation of T cells. This previously unrecognized property of ES cell‐derived HPC s could positively enhance the engraftment of ES cell‐derived HPC s across MHC barriers by preventing rejection.