TY - JOUR
T1 - Evidence for functional inter-relationships between FOXP3, leukaemia inhibitory factor, and axotrophin/MARCH-7 in transplantation tolerance
AU - Muthukumarana, Poorni A.D.S.
AU - Lyons, Gary E.
AU - Miura, Yuji
AU - Thompson, Lorraine H.
AU - Watson, Tracy
AU - Green, Colin J.
AU - Shurey, Sandra
AU - Hess, Allan D.
AU - Rosengard, Bruce R.
AU - Metcalfe, Su M.
N1 - Funding Information:
Funding: This work was supported by the Henry Smith Charity, UK (SMM), the Dunhill Medical Trust (SMM), and the Stanley Thomas Johnson Foundation (SMM). It was also was funded in part by NIH 5-RO1-A1-047257-03 (BRR, PADSM), in part by CA15396 from the NCI, NIH (ADS, YM), and in part by NIH Grants P01 HL47053 and R29 HD29471 (GEL). SMM holds the University of Cambridge Grimshaw-Parkinson Lectureship.
PY - 2006/12/20
Y1 - 2006/12/20
N2 - In an ex vivo mouse model, regulatory transplantation tolerance is not only linked to Foxp3, but also to release of leukaemia inhibitory factor (LIF) and to expression of axotrophin (also known as MARCH-7), a putative ubiquitin E3 ligase associated with feedback control of T cell activation and of T cell-derived LIF. Given this coordinate correlation with tolerance, we now ask if Foxp3 expression is influenced by LIF or by axotrophin. In spleen cells from allo-rejected mice we found that exogenous LIF reduced interferon gamma release in response to donor antigen by 50%, but LIF had no direct effect on levels of Foxp3 protein in allo-primed cells that were either tolerant, or aggressive, for donor antigen. However, we did find an effect of axotrophin on Foxp3: in the axotrophin null mouse, thymic Foxp3 transcripts were reduced compared to axotrophin wildtype littermates. To test whether these findings in the mouse were of potential significance in man we measured transcript levels of axotrophin and LIF in peripheral blood cell samples collected for a recently published clinical study concerning haematopoietic stem cell recipients. In controls, human peripheral blood CD4+CD25+cells contained significantly more FOXP3 and axotrophin than CD4+CD25-cells. In bone marrow autograft recipients, where peripheral blood cell samples directly represent both the grafted tissue and the immune response, both FOXP3 and axotrophin negatively correlated with graft versus host disease (GVHD). These data suggest that (i) thymic Foxp3+T cell development is influenced by axotrophin; and (ii) clinical auto-GVHD inversely correlates with axotrophin transcript expression as has been previously reported for FOXP3.
AB - In an ex vivo mouse model, regulatory transplantation tolerance is not only linked to Foxp3, but also to release of leukaemia inhibitory factor (LIF) and to expression of axotrophin (also known as MARCH-7), a putative ubiquitin E3 ligase associated with feedback control of T cell activation and of T cell-derived LIF. Given this coordinate correlation with tolerance, we now ask if Foxp3 expression is influenced by LIF or by axotrophin. In spleen cells from allo-rejected mice we found that exogenous LIF reduced interferon gamma release in response to donor antigen by 50%, but LIF had no direct effect on levels of Foxp3 protein in allo-primed cells that were either tolerant, or aggressive, for donor antigen. However, we did find an effect of axotrophin on Foxp3: in the axotrophin null mouse, thymic Foxp3 transcripts were reduced compared to axotrophin wildtype littermates. To test whether these findings in the mouse were of potential significance in man we measured transcript levels of axotrophin and LIF in peripheral blood cell samples collected for a recently published clinical study concerning haematopoietic stem cell recipients. In controls, human peripheral blood CD4+CD25+cells contained significantly more FOXP3 and axotrophin than CD4+CD25-cells. In bone marrow autograft recipients, where peripheral blood cell samples directly represent both the grafted tissue and the immune response, both FOXP3 and axotrophin negatively correlated with graft versus host disease (GVHD). These data suggest that (i) thymic Foxp3+T cell development is influenced by axotrophin; and (ii) clinical auto-GVHD inversely correlates with axotrophin transcript expression as has been previously reported for FOXP3.
KW - Axotrophin in immune tolerance
KW - Foxp3
KW - LIF
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U2 - 10.1016/j.intimp.2006.09.015
DO - 10.1016/j.intimp.2006.09.015
M3 - Article
C2 - 17161353
AN - SCOPUS:33845305817
SN - 1567-5769
VL - 6
SP - 1993
EP - 2001
JO - International immunopharmacology
JF - International immunopharmacology
IS - 13-14
ER -