title: Embryonic stem cell-derived haematopoietic progenitor cells down-regulate the CD3 ξ chain on T cells, abrogating alloreactive T cells.
abstract: Murine embryonic stem (ES) cell-derived haematopoietic progenitor cells (HPCs) engraft and populate lymphoid organs. In vivo, HPCs 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 HPCs regulate alloreactive T cells. We used the 2C mouse, which expresses a transgenic T-cell receptor against H2-L(d) to determine whether HPCs are deleted by cytotoxic T lymphocytes (CTLs). Previously, we reported that HPCs express MHC class I antigens poorly and do not express class II antigens. In vitro stimulated 2C CTLs failed to lyse H2-L(d) HPCs in a standard 4-hr (51) chromium release assay. Similarly, when the HPCs were tested in an ELISPOT assay measuring the release of interferon-γ by CTLs, HPCs failed to induce CTL degranulation. In addition, mice that were injected with HPCs showed a marked decrease in T-cell responses to alloantigen and CD3 stimulation, but showed a normal response to PMA/ionomycin, suggesting that HPCs impaired T-cell signalling through the T-cell receptor/CD3 complex. Here, we show that HPCs secrete arginase, an enzyme that scavenges l-arginine, leading to metabolites that down-regulate CD3 ζ chain. Indeed an arginase inhibitor partially restored expression of the CD3 ζ chain, implicating arginase 1 in the down-regulation of T cells. This previously unrecognized property of ES cell-derived HPCs could positively enhance the engraftment of ES cell-derived HPCs across MHC barriers by preventing rejection.
authors: University of Iowa Hospitals and Clinics & Iowa City Veterans Affairs Medical Center, Iowa City, IA, USA.
authors: Eun-Mi
authors: EM
authors: Kim
authors: Bob
authors: B
authors: Miyake
authors: Manish
authors: M
authors: Aggarwal
authors: Ruth
authors: R
authors: Voetlause
authors: Maia
authors: M
authors: Griffith
authors: Nicholas
authors: N
authors: Zavazava
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000276:immunology*; D015536:Down-Regulation; D053595:Embryonic Stem Cells / Q000166:cytology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000276:immunology*; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D017252:CD3 Complex
keywords: T-cell down-regulation; arginase; embryonic stem cells