Treg versus Th17 lymphocyte lineages are cross-regulated by LIF versus IL-6

• DOI: 10.4161/cc.8.9.8348
• Publication Date: 2011-01-20T11:54:50Z
• Authors: Wenda Gao; Lorraine Thompson; Qiang Zhou; Prabhakar Putheti; Tarek M. Fahmy; Terry B. Strom; Su M. Metcalfe
• Keywords: 0301 basic medicine; Leukemia Inhibitory Factor Receptor alpha Subunit; Interleukin-6; Ubiquitin-Protein Ligases; Models, Immunological; Forkhead Transcription Factors; T-Lymphocytes, Helper-Inducer; Leukemia Inhibitory Factor; T-Lymphocytes, Regulatory; Mice; 03 medical and health sciences; Phenotype; Animals; Humans; Cell Lineage

Within the immune system there is an exquisite ability to discriminate between "self" and "non-self" that orchestrated by T lymphocytes. Discriminatory pathways guide differentiation of these lymphocytes into either regulatory (Treg) or effector (Teff) cells, influenced cues from naïve cell's immediate micro-environment as it responds cognate antigen. Reciprocal may lead commitment cells protective tolerance-promoting Treg, pro-inflammatory Th17 phenotype. Primary activation CD4+ stimulates their release leukaemia inhibitory factor (LIF), Treg continue LIF in response antigen, implying a role for tolerance. In apparent contrast interleukin-6 (IL-6), although very closely related LIF, promotes maturation cells. Here we show IL-6 behave polar opposites promoting lineages. augmented Foxp3 expression, lineage transcription factor, suppressed IL-6-induced IL-17A protein release: prevented expression receptor subunit, gp190, at two levels, firstly repressing gp190 secondly inducing massive upregulation axotrophin/MARCH-7, novel E3 ubiquitin ligase involved regulation. vivo, anti-LIF treatment reduced donor-specific recipients foreign spleen Conversely, single dose biodegradable nanoparticles, targeted CD4, successfully manipulated LIF/IL6 axis towards development Foxp3+Treg. The implications therapy are profound, harnessing endogenous regulation paracrine delivery vivo.