CD8 t cell mediated induction of interleukin 12p70 production by dendritic cells

CONTROL OF DENDRITIC CELL INTERLEUKIN-12 PRODUCTION BY CD8 T CELLS WONG KOK LOON (B.Sc (Hons)), NUS A THESIS SUBMITTED FOR THE DEGREE OF DOCTOR OF PHILSOPHY Summary IL-12 is the central cytokine in the initiation and maintenance of a Th1 immune response The production of IL-12p70 by DCs during T cell priming is crucial for the development of Th1 responses Hence, control of DC IL-12p70 production is key for the development of Th1 immunity DC activity can be influenced through direct and indirect interaction with other effector immune cells This results in the delivery of “feedback” signals that can influence the activation status of the DC and thus the outcome of the adaptive immune response While CD8 T cells are primarily known as cytotoxic T cells, their ability to modulate immune responses through interactive feedback with DCs has also been described Of particular interest in this study was the ability of CD8 T cells to promote the production of IL-12 during their interaction with DCs Though previous studies had shown that CD8 T cells had a direct influence on DC IL-12p70 production, they were not without their limitations First, all the DCs utilized so far were generated from DC precursors using GM-CSF and IL-4 It is now known that these DCs not represent lymphoid resident DCs, which consist of a heterogeneous mix of DC subtypes The ability of CD8 T cells to modulate IL-12p70 production with these DCs is not known Second, while IFN-γ was found to be the main factor involved in DC IL-12p70 priming, other studies suggests that this could occur through additional mechanisms It is also unclear if the immune status of CD8 T cells, i.e naïve, activated or memory was important for the ability of CD8 T cells to prime DCs for IL-12p70 Finally, it is uncertain in what immunological context CD8 T cells could influence DCs for IL-12p70 production In this study, we set up an in vitro system to study the effects of CD8 T cells on splenic DC IL-12p70 production during an antigen specific interaction We find that mouse splenic DCs respond to CD8 T cells with IL-12p70 production only when DCs were concurrently stimulated with TLR ligands Different TLR ligands cooperated with CD8 T cells for IL-12p70 production to different extents In particular, CpG was most effective for the induction of IL-12p70, while other TLR ligands, like LPS, were only moderately effective We also found the immune status of the CD8 T cells was important for priming DCs for IL-12p70 production Pre-activation of CD8 T cells was required for effective DC IL-12p70 priming with LPS With CpG, naturally occurring memory CD8 T cells were superior to naïve CD8 T cells for the induction of IL-12p70 Furthermore, we also show that apart from IFN-γ, CD8 T cells also use CD40L, GM-CSF and TNF-α to prime DCs for IL-12p70 production Of the splenic DC subsets, CD8α+ DCs were the primary source of IL-12p70, demonstrating the specialized role of the CD8α+ DC subset in this process Interestingly, CD8α+ DCs are also implicated as the principle DC subset for crosspresentation and cross-priming cytotoxic CD8 T cell responses Our study describes a novel pathway for the induction effective IL-12p70 responses to cross-presented antigens Overall, this study showed that CD8 T cells have the capacity to modulate DC IL-12p70 in the presence of microbial stimuli that triggers DC TLRs It is possible that during the course of an infection, activated or memory antigen specific CD8 T cells could provide essential stimuli to DCs for the production of IL-12p70 that result in protective Th1 responses The current study furthers the understanding of how CD8 T cells can influence DCs, opens up new avenues of research and is useful for the development of therapeutics that seek to promote cell mediated immunity or suppress allergic immune responses Acknowledgements Being able to write this acknowledgment means so much to me It means I am at the end of the road to fulfilling my childhood dream of finally becoming a “doctor” Someone once told me a PhD is your passport to the world, the real beginning as a scientist But for every new beginning, there is an end It was a journey that I shared with so many wonderful people that are now my dearest friends To Prof Kemeny, I will always remember the day when I first approached you Given the desperate circumstances, I am etherally grateful for the fact that you did not turn me down I am also grateful for the opportunities you had given me, and the freedom to pursue my own research interests Though I know I don’t live up to your every expectation, your supervision has made me into a much stronger, tougher person that is now ready to face the world To Dr Paul, thanks for being there for me when I needed help the most, especially for teaching me experimental techniques, the fine art of manuscript writing and invaluable advice on how to be a scientist and to science You had certainly played a big role And you know what, we are both new fathers! To Dr Veronique, though we only communicated a few times, I felt that I learnt a lot each from each communication Thanks for your stories of inspiration and perseverance that kept me going during tough times, and thanks for trusting me and my judgement Here’s wishing you many many wonderful years of fulfilling research and family life To Shuzhen, thanks for the times we shared Knowing you has been a life changing experience for me Thank you for vetting my thesis, which is one “small” thing out of so much that you had done To Fei Chui, it is always inspiring to see the fighter that you are Thanks also for all the motherly care you had given, which reminds me on how a mother hen take cares of her hatchlings And finally, a real hatchling is coming! To Issac, thanks for being such a great buddy and activity partner! From soccer, playing computer games to eating at BJ, what else could a buddy ask for? So what now? To Adrian, thanks you for always being so honest and skeptical about almost everything Though you have strong opinions about things, you almost always end you sabotaging people when they listen to you I find that very hilarious and that is the most endearing quality about you By the way, welcome to fatherhood! To Yafang, thanks for listening to me talk, complain and worry about things, you are so adorable and with your shoes that ring and everything Your sky high IQ and streetwise-ness that make me “so scared” of you, because I think that you know things that I don’t know you know! To Zhenying, you seem to be so innocent and honest, but yet I know you enjoy it most when you crack the most awarkward of jokes just to make me flabbergasted! I really enjoyed your company and thanks for hearing out me out when I am having problems *Wink* To Kenneth and Richard, thanks for tolerating my “bad attitude” towards you and my constant barrage of rude remarks It was good fun and sometimes you just need a punching bag in life, which happens to be you guys Kenneth, you are one of the nicest persons I had ever met, always thinking of others and putting them first over yourself Could you be more human and show your selfish side once a while? To Melissa, you are everything that a co-worker would ask for Though I find the word “obedience” awkward, it was your greatest asset to me You had certainly had come a long way and perhaps it is a good time for you to find your independence To Pey Yng and Chris, thanks for continuing the work and taking a special interest in the molecular side of things To Javier, thanks for being such an easy going person and lending me your computer games but without the CD keys To Benson and Elsie, thanks for keeping the lab running smoothly I would also like to thank other friends including Angeline, Karwai, Xilei, Lin Gen, Jason, Boon King, Olivia and others not mentioned who had made my life so much more interesting Special thanks goes to Jane Thanks for enduring so much for me and tolerating all my nonsense that I throw at you when I am fustrated Thanks for always being there, always finally listening to me and for taking care of Kaizer, which is no small task To Kaizer, thanks for making my life such a mess, but without which I wouldn’t have known the true value of love, life and God Do grow up to be a virtuous man Thanks to Jane’s family, Richard and Lily, though I know you hate it when I address you by your names Your care, help and support was and is still invaluable To mum and dad, thanks for brining me up so that I could see this day, and my bother, may you live a happy and fulfilling life Abbreviations 7-AAD 7-Amino-actinomycin D AP alkaline phosphatase APC antigen presenting cell APC allophycocyanin BM bone marrow BSA bovine serum albumin CD Cluster of Differentiation cDC conventional dendritic cell CpG cytosine (unmethylated)-phosphate-guanosine CTL cytotoxic T lymphocyte DC dendritic cell EDTA ethylenediaminetetraacetic acid ELISA Enzyme Linked Immunosorbent assay FACS Fluorescence activated cell sorting FCS fetal calf serum Fig Figure FITC fluorescein-5-isothiocyanate GM-CSF Granulocyte Macrophage-Colony Stimulating Factor hi high IFN interferon IRF interferon regulatory factor IL interleukin lo low LPS lipopolysaccharide minutes ml millillitre OT-I OVA257-264-specific T cell with transgenic TCR for MHC I NK natural kkiller O/N overnight mAb monoclonal antibody MACS Magnetic activated cell sorting MHC Major Histocompatibility Class MoDC monocyte derived dendritic cell OVA ovalbumin PBS phosphate buffered saline pDC plasmacytoid dendritic cell PE phycoerythrin PFA paraformaldehyde PMA phorbol 12-myristate-13-acetate pNPP p-nitrophenyl phosphate Poly I:C polyinosinic:polycytidylic acid RPMI Roswell Park Memorial Institute medium rpm round per minute r.t room temperature SAC Staphylococcus aureus Cowan strain I TCR T cell receptor TLR Toll-Like Receptor TNF tumor necrosis factor WT wild type Table of contents Chapter 1: Introduction 17 Interleukin-12 17 CD8 T cells 18 Dendritic cells 20 Heterogeneity of DCs .21 T helper responses: the different flavors 23 Polarization of the immune response by DCs 26 Toll-like receptors .28 TLR stimulation and 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278(41): 39372-39382 195 ... the elimination of infected and tumor cells CD8 T cells start off as naïve T cells that circulate the body after development in the thymus CD8 T cells are activated by encounter with antigen, which... Lambrecht, 2008) Stimulation of epithelial cells via PRRs results in the production of thymic stromal lymphopoietin (TSLP) that directly activates DCs to prime CD4 T cells to differentiate into Th2 cells. .. CD8 T cells to enhance DC IL -12p70 production is attributed mainly to the production of IFN-γ by CD8 T cells 36 Chapter 1: Introduction Like NK cells, CD8 T cells can also negatively regulate