Question 3 (3.5 points): Multiple sclerosis (MS) is an autoimmune disease in whi

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Question 3 (3.5 points): Multiple sclerosis (MS) is an autoimmune disease in which autoreactive TH cells participate in the destruction of the myelin sheath around neurons in the nervous system. The precise symptoms are variable between individuals, depending on which neurons are affected, but the disease can be very disabling and lead to complete loss of movement and death. Recent work in a mouse model of MS suggests that transplantation of cell precursors of neurons may be a beneficial therapy. Although these immune cells are likely partially protective because they can develop into neuronal cells that replace the myelin sheath, some investigators realized that they play another (perhaps even more important) role. These scientists showed that the neuronal cell precursors secrete a cytokine called Leukemia Inhibiting Factor (LIF). In fact, administration of LIF alone (in the absence of neuronal precursor cells) is sufficient to ameliorate symptoms. To determine if LIF had an effect on T cell activity, investigators added LIF to cultures of T cells from WT mice that were being stimulated under different polarizing conditions (e.g. stimulation if the presence of cytokines that differentiation to distinct helper subsets). They then stained T cells for production of various effector cytokines and analyzed the results by flow cytometry. The data below show their results from WT mouse CD4 T cells polarized to the lineage indicated in either the absence (top panel, control) or presence (bottom panel) of LIF. TH17 REG 22.1 0.6 2.9 1.2 36.9 3.4 7.8 11.2 0.7 2.7 0.6 37.7 5.2 FNY CD4 by oanology, Seventh Edeion 2013 W H Freeman and Company a). (2 points) Which T helper lineage(s) is/are most affected by the addition of LIF? Explain your answer. b). (0.5 points) Why might these results explain the beneficial effect of LIF on disease severity? c). (1 point) Knowing what you know now about the molecular events that influence T cell differentiation, speculate on the molecular basis for the activity of LIF.

Explanation / Answer

a) TH 17 cells are most affected. From the flow cytometry its obvious that TH 17 are less in number compared to control (nearly half). Over activation of TH 17 cells are implicated in autoimmune diseases and inflammation. LIF is a IL-6 family cytokine involved in the proper activation of naive TH 17 cells, which is also called nonpathogenic or protective TH 17 cells or Treg 17 cells.  Interferon gamma stimulates TH1 and IL4 stimulates TH2 helper cell differentiation, IFN? and IL4 shown to inhibit TH17 differentiation, if there is a change or less production of these cytokines, TH17 differentiate to pathogenic cells by producing auto cytokines by them like IL-23 and IL-1?, IL-21 which act on TH17. Hence TH17 cells differentiation and excess activity (called pathogenic cells) has to be moderated by cytokines like IFN? and IL4. TH17 cells

b) LIF can be administered to control/moderate the TH17 cells not to differentiate in to autoimmune pathogenic cells, the effect can be temperory but it will help the patient to ameliorate the effect which may save the life for time being, before embarking on a trained T cell therapy using naive T cells from embriyonic stem cells.  

c) As described in part a)  IFN? and IL4 are involved in proper differentiation of naive TH17 cells to Treg17 cells, however this is possible only in the combinatorial presence of transforming growth factor-? (TGF-?) and IL-6,   recollect LIF is a IL-6 cytokine helpful in proper differentiation of TH17 cells. Here Treg17 cells secrete TGF-?, hence LIF (IL-6) acting in combination with TGF-?. TGF-? in combination with IL-6 induce expression of the transcription factor RORC, which is a nuclear receptor with a ligand binding pocket it may bind to IL-17 promoter.   

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