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CD8 T Cell Differentiation During Immune Responses

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CD8 T Cell Differentiation During Immune Responses UNIVERSITÉ PARIS DESCARTES FACULTÉ DE MEDECINE-site Necker INSERM U1020 (ex U591) _______________________________________________________________________ THÈSE Pour obtenir le grade de DOCTEUR Sciences de la Vie et de la Santé Discipline: Immunologie École Doctoral: Gc2iD Présentée et soutenue publiquement par Sara Sofia de Campos Pereira Lemos Le 23 Mai 2014 CD8 T cell differentiation during immune responses Jury: Dr. Jacqueline MARVEL Rapporteur Dr. Sylvie GUERDER Rapporteur Dr. Jérôme DELON Examinateur Dr. Nicolas BLANCHARD Examinateur Dr. Benedita ROCHA Directeur de these 1 To a wonderful person, an extraordinary woman and an amazing mother... my mother, Arlete Pereira “The first precept was never to accept a thing as true until I knew it as such without a single doubt.” René Descartes (French philosopher and scientist) “We live where no one knows the answer and the struggle is to figure out the question” Joshua Schimel (in “Writing Science” book). “ To be great, be whole; Exclude nothing, exaggerate nothing that is not you. Be whole in everything. Put all you are Into the smallest thing you do. So, in each lake, the moon shines with splendor Because it blooms up above.” Fernando Pessoa (Portuguese poet) “The beauty of life is not about finding something big enough, but rather on finding something deep enough! Sara Lemos (a dreamer!) 2 Acknowledgments My very first and respectful acknowledgment I owe to an extraordinary scientist and remarkable person: my supervisor Benedita ROCHA. Thank you for accepting me in your lab, for supervising this work, for all the opportunities given to grow as a PhD student and as a person, for all the freedom at the bench, and yet for always pushing me forward. It was such an HONOR and CHALLENGE to work with you! To all jury members, a special thank you for accepting to evaluate this thesis work. To Jacqueline MARVEL and Sylvie GUERDER a particularly thank you for your precise and critical analyze of my thesis work as rapporteurs. To Jérôme DELON and Nicolas BLANCHARD a special thank you for your patience in waiting for the final version and for revising this work as examinateurs. It was also an HONOR to have all of you judging this work. From Institut Pasteur, I would like to thank Antonio FREITAS for providing us with OT-1 mice, Matthew ALBERT for MyD88-/- mice and Hélène DECALUWE for preparing LCMV and performing the corresponding immunizations. From Necker Institute, I would like to thank Alain CHARBIT at INSERM U1002 for his advice and bacteria expertise, and for using his bacteria lab facilities too. To his team members, thank you for always making me feel truly welcome in a “bacterial” lab (my 2nd lab/home!). Thank you to all members of INSERM U1020 (ex U591). Sophie EZINE for all the B6 Thy1.1 mice given, for pushing my organizational skill to top levels and for always being there to solve lab problems and to guide me in the thesis manuscript/defense procedures. Orly AZOGUI for truly understanding my complainings about FlowJo crashes and for always being available to discuss science! (a special thanks for precious help with my thesis summary in French too). Florence VASSEUR and Pierric PARENT for big help with mice during the lab moving from Necker Institut to Broussais Hospital. Agnes LEGRAND for precious help on single-cell multiplex RT-PCR experiments, for teaching me SDS program, for all your sincerity, efficiency and friendship. To all secretaries, for patience with my complicated orders of new products or mice. Chantal for helping me with DNA extractions for mice genotyping (a tremendous time consuming job to do alone!). Benoir for efficiently providing material disappeared at the last minute. Evelyn, for always reminding me that the world is round and that sometimes we need to say a big NO (I should practice it more!!!). To the new members of the new INSERM U1151-team 13, Flora ZAVALA and Sarantis KORNIOTIS, a big thank you for your kindness, happy “bonjours” and powerful “courage Sara, c’est bientôt la fin!”, during the last tough weeks of thesis writing! To Cesar EVARISTO and Patricia SANTOS for being awesome "lab parents" to me and Miguel, for NEVER having denied a scientific discussion, for your truth friendship and for all the tuga's dinners around Paris! To Cesar, extra thanks for being ALWAYS available to teach me: at 4 am when dilacerating spleens to plate; at 2 am when fighting for a 3rd (not broken) Canto to not lose our incredible amount of work; and even at 7.000 Km away, for answering all my specific questions, or sending me your data to combine with mine (what a nightmare!). My gratefulness and respect to you are infinite! Thanks for the astonishing book “Writing Science”. To Patricia extra thanks for your objectivity, sincerity and CLEVER talks either about science or life! I particularly enjoyed the ones in the corridors or those seated on FACS flow boxes! To Miguel FERREIRA, a true "brother in science", thank you for the immense patience to discuss with me homologous recombination tricks (as well as a bunch of other scientific stuff) and for being always on 3 my right side (of the office) to listen, to talk, to share, or simply just to be there with a true friendship. An extra thanks for being the only one TRULY understanding the meaning of a back pain, or a cold feeling when huge experiments take more than 20h. (Contributions to my French metro-poetry posters’ collection, not forgotten!). To Vanessa ZEPPONI, my "French lab sister", an immense thank you for always being there, at my left side (of the bench), for teaching me new concepts and views about life, and for ALL FUNNY moments lived in the lab and around Paris! An extra thank you for beers or Japanese moments of friendship (Disneyland and a lot of not taken T3 tramways moments too!) and also for always helping me with French language, essential to survive in the lab and in the Paris-quotidian life! To Hsueh SUNG, a big thank you for being always available to answer, at distance, my 1001 questions about practical details of the CD8 inflammatory project. Thanks a lot for all the true friendship, PATIENCE AND RESPECT (it was a pity that we couldn´t work together on the bench!). To all current postdocs, an enormous thank you for the “mental support” during my thesis writing (advice, tricks and frustrations included! you know how hard it was to leave my lovely bench!). Alessia GALGANO for all the discussions about molecular biology and lab (dis)organization. Marie CHERRIER, for sharing with me much more than the office in this last year, for all your sincerity, advice, friendship, scientific talks, and good lab mood (once one is an OUTSTANDING person, one will be an outstanding group leader too. All the best!). To Gerald KRENN and Alexander BARINOV… to you “my” guys… My gratitude and respect are INFINITE. A truthful thank you for all your friendship, your sincerity, wise advice, men’s objectivity, confidence and beers that always comforted me! I’ll miss a lot our Austro-Russian-Luso “canteen-gang”!!! A special thanks for the multicultural "soirées" in the company of your wives too. To Ricarda KRENN, a special thanks for reviewing my English writing. To Pedro GONÇALVES for friendship and all the supporting: Write Sara!!! Write Sara!!! I’m still deeply grateful to Gerald, Alexander, Pedro and Vanessa for helping me when my computer broke down 3 days before sending my manuscript to evaluation! (what a panic attack!). To the current students Victoria M. LOPEZ and Thomas HARBONNIER, thank you for all the good moments, friendship, and “student’s solidarity”! (good luck!!!). To former members of the Necker lab with whom I also shared big moments around pipettes, reagents and laughs, a sincere thank you for being so nice with me: Sylvain MEUNIER, Laetitia PEAUDECERF, Lamina SKHIRI, Marie BÉDORA, Amine BOUDIL, and Kateryna KOZYRYTSKA. Special thanks to all the" petits" that were quite big friends: Paula MARTINS, Cédric DONATHELLO and Coraline CANIVET for the "on mange the hors!", Yann BECKER for "poker face" laughing moments and Laurent BEZIAUD for COMEDY moments and for being so present and supportive (and I am so sorry for being always late! - I’m a disaster in terms of orientation !!!) (good luck for your thesis writing!). An IMMEASURABLE thank you to my (maternal) FAMILY! My MOTHER, for unconditional love and support during every single day of my life! My UNCLES, those who welcomed me several times at the airport, or those who always made my favorite chocolate cake for departure! My COUSINS, those who always say to me “Sara wake up! You live like a nomad!”, those who never deny card games during our gatherings of family dinners, and yet, the ones who never let me sing alone (in particular Linkin Park songs!) and always gave me those sincere and powerful hugs! My maternal GRANDPARENTS and GREAT-UNCLES for always being there with open loving arms. To other RELATIVES who constantly 4 ask my mother “how is Sara, there? when is she back?” a special thanks too. When one grows up in a small village, your NEIGHBORS are also your family, thus a big thank you for all the Sangemil-Penalva- Viseu’s love and care. To my true and UNFORGETTABLE Biochemistry friends since the University of Coimbra era, an immeasurable thank you too, for being always so present in my life with a sincere friendship, even if more than 1500Km away! Thank you for being ALWAYS there. It is splendid how we stay so “covalent bonded” after all these years (not even an electron moved out from their orbit/our friendship!).
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