Our recent work has demonstrated that the immunosuppressive drug rapamycin selectively affects the CsA-resistant pathway. Our initial studies have focused on the mechanism of activation of the IL-2 gene in a CsA-resistant manner. We found that the effect of rapamycin on the IL-2 expression was due to alteration in IL-2 mRNA stability. More recently, we have also shown that activation of T cells by IL-12 is resistant to CsA, but sensitive to rapamycin. As the intracellular target of rapamycin is mTOR (mammalian target of rapamycin), we are investigating the mechanism of activation of mTOR during T cell activation. Our preliminary data indicate that PKC-theta plays an important role in turning on mTOR downstream signaling. Regarding the physiological role of the resistant pathway, we have observed the effect of cytokine signaling, particularly the combination of IL-12 and IL-18 but not individual cytokine alone, in activating resting human peripheral blood T cells in producing IFN-g in a CsA-resistant, but rapamycin-sensitive manner. Bothe nave and memory CD4+ T cells are responsive to IL-12 plus IL-18 stimulation. This cytokine-mediated activation of resting T cells is independent of antigen. Intracellular staining reveals a small percentage of resting CD4+ T cells capable of producing IFN-g in response to IL-12 plus IL-18. We have shown that CD4+IL-18Ra+ cells are the main populations responsive to IL-12 plus IL-18. The expression of IFN-g induced by IL-12 and IL-18 is sensitive to rapamycin and SB203580, indicating the possible involvement of mTOR and p38 MAP kinase, respectively, in this synergistic pathway. We have also shown that IL-12 plus IL-18-induced IFN-g mRNA expression is independent of new protein synthesis and independent of GADD45b and g. We have also shown that CXCL12-mediated T cell migration requires mTOR pathway. CXCL12 is a strong chemokine that governs major immune cell migration and trafficking. We are currently investigating the role of mTOR pathway in mitochondrial respiration and T-cell differentiation using splenic T cells from p70S6K1 KO mice.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000115-13
Application #
8552319
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2012
Total Cost
$680,863
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Sasaki, Carl Y; Chen, Gang; Munk, Rachel et al. (2016) p(⁷⁰S⁶K¹) in the TORC1 pathway is essential for the differentiation of Th17 Cells, but not Th1, Th2, or Treg cells in mice. Eur J Immunol 46:212-22
Eitan, Erez; Hutchison, Emmette R; Greig, Nigel H et al. (2016) Corrigendum to "Combination therapy with lenalidomide and nanoceria ameliorates CNS autoimmunity", [Exp. Neurol. 273 (2015), 151-160]. Exp Neurol 280:121
Hou, Yan; Ghosh, Paritosh; Wan, Ruiqian et al. (2014) Permeability transition pore-mediated mitochondrial superoxide flashes mediate an early inhibitory effect of amyloid beta1-42 on neural progenitor cell proliferation. Neurobiol Aging 35:975-89
Carey, Robyn M; Blusztajn, Jan K; Slack, Barbara E (2011) Surface expression and limited proteolysis of ADAM10 are increased by a dominant negative inhibitor of dynamin. BMC Cell Biol 12:20
Munk, Rachel; Ghosh, Paritosh; Ghosh, Manik C et al. (2011) Involvement of mTOR in CXCL12 mediated T cell signaling and migration. PLoS One 6:e24667
Munk, Rachel B; Sugiyama, Katsuki; Ghosh, Paritosh et al. (2011) Antigen-independent IFN-γ production by human naïve CD4 T cells activated by IL-12 plus IL-18. PLoS One 6:e18553