title: Kinome Profiling of Regulatory T Cells: A Closer Look into a Complex Intracellular Network.
abstract: Regulatory T cells (Treg) are essential for T cell homeostasis and maintenance of peripheral tolerance. They prevent activation of auto-reactive T effector cells (Teff) in the context of autoimmunity and allergy. Otherwise, Treg also inhibit effective immune responses against tumors. Besides a number of Treg-associated molecules such as Foxp3, CTLA-4 or GARP, known to play critical roles in Treg differentiation, activation and function, the involvement of additional regulatory elements is suggested. Herein, kinase activities seem to play an important role in Treg fine tuning. Nevertheless, our knowledge regarding the complex intracellular signaling pathways controlling phenotype and function of Treg is still limited and based on single kinase cascades so far. To gain a more comprehensive insight into the pathways determining Treg function we performed kinome profiling using a phosphorylation-based kinome array in human Treg at different activation stages compared to Teff. Here we have determined intriguing quantitative differences in both populations. Resting and activated Treg showed an altered pattern of CD28-dependent kinases as well as of those involved in cell cycle progression. Additionally, significant up-regulation of distinct kinases such as EGFR or CK2 in activated Treg but not in Teff not only resemble data we obtained in previous studies in the murine system but also suggest that those specific molecular activation patterns can be used for definition of the activation and functional state of human Treg. Taken together, detailed investigation of kinome profiles opens the possibility to identify novel molecular mechanisms for a better understanding of Treg biology but also for development of effective immunotherapies against unwanted T cell responses in allergy, autoimmunity and cancer.
authors.affiliation: Department of Dermatology, University Medical Center Mainz, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Tuettenberg
authors.affiliation: Department of Dermatology, University Medical Center Mainz, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Susanne A
authors.initials: SA
authors.lastname: Hahn
authors.affiliation: Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center Mainz, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Johanna
authors.initials: J
authors.lastname: Mazur
authors.affiliation: Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center Mainz, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Aslihan
authors.initials: A
authors.lastname: Gerhold-Ay
authors.affiliation: Department of Developmental Bioengineering, University of Twente, Enschede, the Netherlands.
authors.forename: Jetse
authors.initials: J
authors.lastname: Scholma
authors.affiliation: Department of Dermatology, University Medical Center Mainz, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Iris
authors.initials: I
authors.lastname: Marg
authors.affiliation: Institute for Immunology, University Medical Center Mainz, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Ulges
authors.affiliation: Department of Dermatology, University Medical Center Mainz, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Satoh
authors.affiliation: Institute for Immunology, University Medical Center Mainz, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Bopp
authors.affiliation: Pepscope BV, Utrecht, The Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Joore
authors.affiliation: Department of Dermatology, University Medical Center Mainz, Johannes Gutenberg-University, Mainz, Germany.
authors.forename: Helmut
authors.initials: H
authors.lastname: Jonuleit
mesh_terms: D000328:Adult; D015153:Blotting, Western; D003598:Cytoskeletal Proteins / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D006801:Humans; D016014:Linear Models; D008213:Lymphocyte Activation / Q000276:immunology; D011494:Protein Kinases / Q000378:metabolism*; D040901:Proteomics; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000201:enzymology*; D000099149:Ezrin
chemical_list: D003598:Cytoskeletal Proteins; D066246:ErbB Receptors; D011494:Protein Kinases; D000099149:Ezrin