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Ccl17-Dependent Release of Ccl3 Restrains Regulatory T Cells Thereby Aggravating Atherosclerosis

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Ccl17-Dependent Release of Ccl3 Restrains Regulatory T Cells Thereby Aggravating Atherosclerosis From the Institute for Cardiovascular Prevention (IPEK) of the Ludwig-Maximilians-Universität München Director: Univ.-Prof. Dr. med. Christian Weber Ccl17-dependent release of Ccl3 restrains regulatory T cells thereby aggravating atherosclerosis Dissertation zum Erwerb des Doctor of Philosophy (Ph.D.) an der Medizinischen Fakultät der Ludwig-Maximilians-Universität München Submitted by M.Sc. Carlos Neideck from Taió in Santa Catarina, Brazil on 21.03.2018 Supervisor: Prof. Dr. med. Christian Weber Second evaluator: Prof. Dr. rer. nat. Jürgen Bernhagen Dean: Prof. Dr. Reinhard Hickel Date of oral defense: 23.07.2018 Affidavit Neideck, Carlos ______________________________________________________________________ Name, Surname ______________________________________________________________________ Street ______________________________________________________________________ Zip Code, Town ______________________________________________________________________ Country I hereby declare, that the submitted thesis entitled: “Ccl17-dependent release of Ccl3 restrains regulatory T cells thereby aggravating atherosclerosis.” is my own work. I have only used the sources indicated and have not made unauthorized use of services of a third party. Where the work of others has been quoted or reproduced, the source is always given. I further declare that the submitted thesis or parts thereof have not been presented as part of an examination degree to any other university. Munich, 25.07.2018 Carlos Neideck Place, date Signature doctoral candidate Confirmation of congruency between printed and electronic version of the doctoral thesis Neideck, Carlos ______________________________________________________________________ Name, Surname ______________________________________________________________________ Street ______________________________________________________________________ Zip Code, Town ______________________________________________________________________ Country I hereby declare that the electronic version of the submitted thesis, entitled: “Ccl17-dependent release of Ccl3 restrains regulatory T cells thereby aggravating atherosclerosis.” is congruent with the printed version both in content and format. Munich, 25.07.2018 Carlos Neideck Place, date Signature doctoral candidate The results of this work will be, or are partly published in: Neideck C, van der Vorst E, Mandl M, Jansen Y , Blanchet X, Faussner A, Megens RT, Drechsler M, Weber C, Döring Y. “Ccl17-dependent release of Ccl3 restrains regulatory T cells thereby aggravating atherosclerosis.” (in preparation) von Hundelshausen P, Agten S*, Eckardt V*, Schmitt M*, Blanchet X*, Ippel H*, Neideck C*, Bidzhekov K*, Wichapong K*, Faussner A, Drechsler M, Grommes J, van Geffen J, Li H, Leberzammer J, Naumann R, Dijkgraaf I, Nicolaes G, Döring Y, Soehnlein O, Lutgens E, Heemskerk J, Koenen R, Mayo K, Hackeng T, Weber C. (2017) “Chemokine interactome mapping enables tailored intervention in acute and chronic inflammation.” Science Translational Medicine 9(384):eaah6650. * denotes equal contribution Table of Content ______________________________________________________________________ Table of Content Table of Content ................................................................................................................ I Abbreviations ................................................................................................................... V List of Figures ................................................................................................................. IX List of Tables .................................................................................................................. XI 1. Introduction ................................................................................................................ 1 1.1. The immune system ............................................................................................ 2 1.1.1 The innate immune system ........................................................................... 2 1.1.2. The adaptive immune system ....................................................................... 3 1.2. Cells of the immune system ................................................................................ 5 1.2.1 Dendritic cells ............................................................................................... 6 1.2.2 T cells ......................................................................................................... 10 1.3. The chemokine – chemokine receptor system .................................................. 17 1.3.1 Ccl17 – Ccr4 ............................................................................................... 21 1.3.2 Ccl5 and its receptors ................................................................................. 22 1.3.3 Chemokine heterodimerization ................................................................... 22 1.4. Atherosclerosis .................................................................................................. 23 1.4.1 Pathomechanisms of atherosclerosis ......................................................... 25 1.4.2 Dendritic cells in atherosclerosis................................................................. 26 1.4.3 T cells in atherosclerosis ............................................................................ 30 2. Materials and methods............................................................................................. 35 2.1. Materials ............................................................................................................ 35 2.1.1 General equipment ..................................................................................... 35 2.1.2 Consumables .............................................................................................. 35 2.1.3 Buffers, chemicals, media, solutions ........................................................... 36 I Table of Content ______________________________________________________________________ 2.1.4 Peptides, antagonists and antibodies ......................................................... 37 2.1.5 Reagent kits and miscellaneous ................................................................. 40 2.1.6 Mice ........................................................................................................... 41 2.2. Methods ............................................................................................................ 42 2.2.1. In vivo experiments .................................................................................... 42 2.2.2. Protein assays ............................................................................................ 45 2.2.3. Functional assays ...................................................................................... 48 2.2.4. Statistical analysis ...................................................................................... 50 3. Results .................................................................................................................... 51 3.1. Discrepancy between Ccl17 deficiency and Ccr4 deficiency ............................ 52 3.1.1. Deficiency of Ccl17 reduces atherosclerosis in Apoe-/- mice by restraining Tregs .......................................................................................................... 52 3.1.2. Deficiency of Ccr4 does not reduce atherosclerosis in Apoe-/- mice and has no effect on regulatory T cell populations. .................................................. 55 3.1.3. Hematopoietic deficiency of Ccr4 increases atherosclerotic lesions in Apoe-/- mice through hypocholesteremia ............................................................... 58 3.1.4. Ccl17 induces T cell migration via Ccr4 but does not affect Tregs directly. 62 3.1.5. Summary and hypothesis. .......................................................................... 64 3.2. Searching for a secondary mediator. ................................................................ 65 3.2.1. Ccl17-dependent secretion of Ccl3 and Cxcl10 by DCs. ............................ 65 3.2.2. Deficiency of Ccl3 reduces atherosclerosis in Apoe-/- mice by restraining Tregs and thereby phenocopies Ccl17 deficiency. ..................................... 71 3.2.3. Recombinant Ccl3 reverses effects of Ccl17 deficiency. ............................ 74 3.2.4. Deficiency of Ccr1 reduces atherosclerosis in Apoe-/- mice by restraining Tregs and thereby phenocopies Ccl17 and Ccl3 deficiency. ...................... 76 3.2.5. Identifying an alternative receptor for Ccl17. .............................................. 79 3.3. Heteromeric complexes and their effects on leukocyte function ....................... 83 II Table of Content ______________________________________________________________________ 3.3.1. Ccl17 forms heteromeric complexes with Ccl5 ........................................... 83 3.3.2. Ccl5-Ccl17 heterodimers induce more efficient T cell arrest ....................... 86 3.3.3. Ccl5-Ccl17 heterodimers provoke more efficient binding of Ccl17 to Ccr4 . 87 3.3.4. Ccl5-Ccl17 heterodimers provoke heterodimerization of the receptors Ccr4 and Ccr5 ..................................................................................................... 88 3.3.5. Synergistic effect of Ccl5-Ccl17 heterodimers in T cell transmigration is dependent on Ccr4 and Ccr5 heterodimerization. ...................................... 89 4. Discussion ..............................................................................................................
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