P6	Calcium-dependent T-cell activation in multiple sclerosis

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The figure above show an analysis by flow cytometry of cells producing cytokines IFN-g, or IL-17 or expressing the transcription factor FoxP3 (left panel) and of store operated Ca2+ entry (right panel) from human CD4 stimulated and cultured under conditions for polarizing into Treg (red), Th1 (grey),or Th17 (green) compared to the non-polarized cells (black).

Project 6 analyses calcium signalling signatures, store-operated calcium entry mechanisms and their redox sensitivity as well as cleavage targets of caspases in healthy human and rodent Th1, Th2, Th17 and Treg cells compared to those obtained during autoimmune optic neuritis and MS.

These findings will be correlated with T cell pathogenicity, T cell subtype fate determination, the ability of T cells to cross the blood brain barrier (BBB), and the extent of neurodegeneration.

Blood samples from patients with acute optic neuritis and/or different stages of MS will be obtained from Diem (project 1), the clinical collaboration partner, who will also perform clinical follow-ups. Samples from rodents with optic neuritis and EAE will be provided by project 3 (Fairless/Draguhn; Neurology Heidelberg/Physiology Heidelberg) and project 4 (Winkler/Williams; Neurology Heidelberg). In collaboration with project 5 (Schmitz; Anatomy Homburg) localization of Unc119 in T cell synapse formation will be studied. The project will also interact with project 9 (Kirchhoff; Physiology Homburg) on 2P-LSM of T cells at the BBB and on Orai/STIM expression analyses in glia.

PrincipalInvestigators

Publications

Alansary D, Bogeski I, Disteldorf BM, Becherer U, Niemeyer BA (2010) ATP modulates Ca2+ uptake by TRPV6 and is counteracted by isoform-specific phosphorylation. FASEB J 24:425-35

Alansary D, Kilch T, Holzmann C, Peinelt C, Hoth M, Lis A (2014) Measuring endogenous ICRAC and ORAI currents with the patch-clamp technique. Cold Spring Harb Protoc 2014:630-7

Bogesi I, Kilch T, Niemeyer BA (2012) ROS and SOCE: recent advances and controversies in the regulation of STIM and Orai. J Physiol 590:4193-200

Bogeski I, Kummerow C*, Al-Ansary D*, Schwarz EC, Koehler R, Kozai D, Takahashi N, Peinelt C, Griesemer D, Bozem M, Mori Y, Hoth M, Niemeyer BA (2010) Differential redox regulation of ORAI ion channels: a mechanism to tune cellular calcium signaling. Sci Signal 3:ra24

Carreras-Sureda A, Cantero-Recasens G, Rubio-Moscardo F, Kiefer K, Peinelt C, Niemyer BA, Valverde MA, Vicente R (2013) ORMDL3 modulates store-operated calcium entry and lymphocyte activation. Hum Mol Genet 22:519-30

Hoth M, Niemeyer BA (2013) The neglected CRAC proteins: Orai2, Orai3, and STIM2. Curr Top Membr 71:237-71

Kilch T*, Alansary D*, Peglow M, Dorr K, Rychkov G, Rieger H, Peinelt C, Niemeyer BA (2013) Mutations of the Ca2+-sensing stromal interaction molecule STIM1 regulate Ca2+ influx by altered oligomerization of STIM1 and by destabilization of the Ca2+ channel Orai1. J Biol Chem 288:1653-64 *equal contribution

Miedere AM*, Alansary D*, Schwär G, Lee P, Jung M, Helms V, Niemeyer BA (2015) A novel splice variant antagonizes stromal interaction molecule (STIM) mediated Ca2+ signalling. Nat Commun, accepted. *equal contribution

Quintana A, Pasche M, Junker C, Al-Ansary D, Rieger H, Kummerow C, Nunez L, Villalobos C, Meraner P, Becherer U, Rettig J, Niemeyer BA, Hoth M (2011) Calcium microdomains at the immunological synapse: how ORAI channels, mitochondria and calcium pumps generate local calcium signals for efficient T-cell activation. EMBO J 30:3895-912

Stanisz H, Saul S, Muller CS, Kappl R, Niemeyer BA, Vogt T, Hoth M, Roesch A, Bogeski I (2014) Inverse regulation of melanoma growth and migration by Orai1/STIM2-dependent calcium entry. Pigment Cell Melanoma Res 27:442-53

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Calcium-dependent T-cell activation in multiple sclerosis

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Prof. Dr. Dr.

Barbara Niemeyer

Dr.

Dalia Alansary