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 determi...
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Published in | Immunology Vol. 142; no. 3; pp. 421 - 430 |
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Main Authors | , , , , , |
Format | Journal Article |
Language | English |
Published |
01.07.2014
|
Online Access | Get full text |
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Summary: | 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. |
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ISSN: | 0019-2805 1365-2567 |
DOI: | 10.1111/imm.12268 |