title: Evidence for functional inter-relationships between FOXP3, leukaemia inhibitory factor, and axotrophin/MARCH-7 in transplantation tolerance.
abstract: 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.
authors.affiliation: Department of Surgery, University of Cambridge, Cambridge, CB2 2QQ, UK.
authors.forename: Poorni A D S
authors.initials: PA
authors.lastname: Muthukumarana
authors.forename: Gary E
authors.initials: GE
authors.lastname: Lyons
authors.forename: Yuji
authors.initials: Y
authors.lastname: Miura
authors.forename: Lorraine H
authors.initials: LH
authors.lastname: Thompson
authors.forename: Tracy
authors.initials: T
authors.lastname: Watson
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Green
authors.forename: Sandra
authors.initials: S
authors.lastname: Shurey
authors.forename: Allan D
authors.initials: AD
authors.lastname: Hess
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Rosengard
authors.forename: Su M
authors.initials: SM
authors.lastname: Metcalfe
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D006086:Graft vs Host Disease / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology; D007378:Interleukins / Q000378:metabolism; D053605:Leukemia Inhibitory Factor / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D018345:Mice, Knockout; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics; D013950:Thymus Gland / Q000276:immunology / Q000378:metabolism; D014181:Transplantation Immunology / Q000235:genetics / Q000276:immunology; D023001:Transplantation Tolerance / Q000235:genetics / Q000276:immunology*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D007378:Interleukins; D053605:Leukemia Inhibitory Factor; D050796:STAT3 Transcription Factor; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007371:Interferon-gamma; C517825:MARCH7 protein, mouse; C517824:MARCHF7 protein, human; D044767:Ubiquitin-Protein Ligases