Embryonic stem cell‐derived haematopoietic progenitor cells down‐regulate the CD3 ξ chain on T cells, abrogating alloreactive T cells. Issue 3 (July 2014)

• Record Type: Journal Article
• Authors: Kim, Eun‐Mi; Miyake, Bob; Aggarwal, Manish; Voetlause, Ruth; Griffith, Maia; Zavazava, Nicholas
• Is Part Of: Immunology. Volume 142:Issue 3(2014:Jul.)
• Page Start: 421
• Page End: 430
• Publication Date: 2014-07
• Subjects: Immunology -- Periodicals
• DOI: 10.1111/imm.12268
• Languages: English
• ISSNs: 0019-2805

Abstract

<abstract abstract-type="main" id="imm12268-abs-0001"> <title>Summary</title> <p>Murine embryonic stem (ES) cell‐derived haematopoietic progenitor cells (HPCs) engraft and populate lymphoid organs. <italic>In vivo</italic>, 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<sup>d</sup> 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. <italic>In vitro</italic> stimulated 2C CTLs failed to lyse H2‐L<sup>d</sup> HPCs in a standard 4‐hr <sup>51</sup>chromium release assay. Similarly, when the HPCs were tested in an ELISPOT assay measuring the release of interferon‐<italic>γ</italic> 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 <sc>l</sc>‐arginine, leading to metabolites that down‐regulate CD3 <italic>ζ</italic> chain. Indeed an arginase inhibitor partially restored expression of the CD3 <italic>ζ</italic> 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.</p> </abstract>