Within the immune system there is an exquisite ability to discriminate between "self " and "non-self " that is orchestrated by T lymphocytes. Discriminatory pathways guide differentiation of these lymphocytes into either regulatory (
Nanog is a stem cell transcription factor required for self-renewal and for maintaining pluripotency, and Nanog itself is regulated at least in part by leukaemia inhibitory factor (LIF)--a pluripotent cytokine of the IL6 family. MARCH-7 is an E-3 ligase linked to regulation of the LIF-receptor in T lymphocytes and T cells from mice that lack expression of MARCH-7 are hyper-responsive to activation signals and show a five-fold increase in LIF activity. Here we ask, does MARCH-7 influence the expression profile of Nanog during the synchronized entry of T cells into the cell cycle? We discovered that lack of MARCH-7 was permissive for Nanog expression at both transcript and protein levels during G₁/S: moreover, addition of exogenous LIF to the MARCH-7 null cells caused a further 13-fold induction of Nanog; other measured transcripts including TGFβ, p53 and STAT3 were relatively unchanged. Since lack of MARCH-7 altered responsiveness to activation signals we sought evidence for pre-existing regulatory miR's that might correlate with MARCH-7 gene dose using head-to-head comparisons between MARCH-7 null, heterozygous and wt spleen cells. 34 miRs were found including miR-346 that is known to target LIF transcripts and miR-346 is one of 16 miRs differentially expressed between hESCs and induced hiPSCs. Of the 34 miRs, 12 were known to be temporally regulated in embryonic nerve cells. In summary, in the absence of MARCH-7 a new signaling pathway is unmasked that involves Nanog expression in the T cell lineage. This is the first demonstration that T cells retain responsiveness to a LIF/Nanog axis and that this axis is linked to MARCH-7.
In an in vivo/ex vivo murine heart allograft model of allo-tolerance versus allo-rejection, that retains the complexity of the in vivo environment, novel molecular links to Foxp3 and tolerance have been revealed. These include leukaemia inhibitory factor (LIF), a member of the IL-6 cytokine family. However, IL-6 itself was linked to allo-rejection. This raises several questions: (i) does LIF play an active role in immune tolerance? and (ii) does the differential between LIF and IL-6 occur within the T cell itself? Using CD4+Foxp3+ Treg (nTreg) from Foxp3-GFP knockin mice we tested the effect of exogenous LIF, versus exogenous IL-6, on the respective lineage-specific transcription factors, Foxp3 (Treg) and RORγt (TH17). LIF supported Foxp3 transcription but not RORγt: in contrast IL-6 profoundly repressed Foxp3 and induced RORγt. For the LIF-specific receptor subunit, gp190, the response to LIF versus IL-6 was the polar opposite: gp190 transcripts were increased by LIF but strongly inhibited by IL-6, a result that indicated a potential mechanism for cross-regulation, wherein IL-6 would reduce LIF signalling by repressing synthesis of the LIF receptor. Overall, we suggest LIF is a nodal regulator of the Treg lineage, acting to oppose IL-6, the nodal regulator of the TH17 lineage. Our discoveries identify novel drug targets and we provide proof of concept using targeted LIF-nanotherapy to enhance donor-specific Treg cells in vivo. Funding BHF, NIHR, NIH, JDRF.
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