ADD references to the il15 section
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@ -1940,6 +1940,149 @@ CONCLUSIONS: We developed a simplified, semi-closed system for the initial selec
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publisher = {Wiley},
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}
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@Article{Stonier2010,
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author = {Spencer W. Stonier and Kimberly S. Schluns},
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journal = {Immunology Letters},
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title = {Trans-presentation: A novel mechanism regulating {IL}-15 delivery and responses},
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year = {2010},
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month = {jan},
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number = {2},
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pages = {85--92},
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volume = {127},
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doi = {10.1016/j.imlet.2009.09.009},
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publisher = {Elsevier {BV}},
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}
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@Article{Osinalde2014,
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author = {Nerea Osinalde and Virginia Sanchez-Quiles and Vyacheslav Akimov and Barbara Guerra and Blagoy Blagoev and Irina Kratchmarova},
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journal = {{PROTEOMICS}},
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title = {Simultaneous dissection and comparison of {IL}-2 and {IL}-15 signaling pathways by global quantitative phosphoproteomics},
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year = {2014},
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month = {sep},
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number = {2-3},
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pages = {520--531},
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volume = {15},
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doi = {10.1002/pmic.201400194},
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publisher = {Wiley},
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}
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@Article{Kennedy2000,
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author = {Mary K. Kennedy and Moira Glaccum and Sandra N. Brown and Eric A. Butz and Joanne L. Viney and Monica Embers and Naoto Matsuki and Keith Charrier and Lisa Sedger and Cynthia R. Willis and Kenneth Brasel and Philip J. Morrissey and Kim Stocking and JoAnn C. L. Schuh and Sebastian Joyce and Jacques J. Peschon},
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journal = {Journal of Experimental Medicine},
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title = {Reversible Defects in Natural Killer and Memory Cd8 T Cell Lineages in Interleukin 15{\textendash}Deficient Mice},
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year = {2000},
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month = {feb},
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number = {5},
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pages = {771--780},
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volume = {191},
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doi = {10.1084/jem.191.5.771},
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publisher = {Rockefeller University Press},
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}
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@Article{Lodolce1998,
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author = {James P Lodolce and David L Boone and Sophia Chai and Rachel E Swain and Themistocles Dassopoulos and Shanthi Trettin and Averil Ma},
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journal = {Immunity},
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title = {{IL}-15 Receptor Maintains Lymphoid Homeostasis by Supporting Lymphocyte Homing and Proliferation},
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year = {1998},
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month = {nov},
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number = {5},
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pages = {669--676},
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volume = {9},
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doi = {10.1016/s1074-7613(00)80664-0},
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publisher = {Elsevier {BV}},
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}
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@Article{MirandaCarus2005,
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author = {Mar{\'{\i}}a-Eugenia Miranda-Car{\'{u}}s and Marta Benito-Miguel and Miguel A. Llamas and Alejandro Balsa and Emilio Mart{\'{\i}}n-Mola},
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journal = {The Journal of Immunology},
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title = {Human T Cells Constitutively Express {IL}-15 That Promotes Ex Vivo T Cell Homeostatic Proliferation through Autocrine/Juxtacrine Loops},
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year = {2005},
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month = {sep},
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number = {6},
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pages = {3656--3662},
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volume = {175},
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doi = {10.4049/jimmunol.175.6.3656},
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publisher = {The American Association of Immunologists},
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}
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@Article{Giri1994,
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author = {J.G. Giri and M. Ahdieh and J. Eisenman and K. Shanebeck and K. Grabstein and S. Kumaki and A. Namen and L.S. Park and D. Cosman and D. Anderson},
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journal = {The {EMBO} Journal},
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title = {Utilization of the beta and gamma chains of the {IL}-2 receptor by the novel cytokine {IL}-15.},
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year = {1994},
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month = {jun},
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number = {12},
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pages = {2822--2830},
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volume = {13},
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doi = {10.1002/j.1460-2075.1994.tb06576.x},
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publisher = {Wiley},
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}
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@Article{Giri1995,
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author = {J. G. Giri and S. Kumaki and M. Ahdieh and D. J. Friend and A. Loomis and K. Shanebeck and R. DuBose and D. Cosman and L. S. Park and D. M. Anderson},
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journal = {The {EMBO} Journal},
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title = {Identification and cloning of a novel {IL}-15 binding protein that is structurally related to the alpha chain of the {IL}-2 receptor.},
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year = {1995},
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month = {aug},
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number = {15},
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pages = {3654--3663},
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volume = {14},
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doi = {10.1002/j.1460-2075.1995.tb00035.x},
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publisher = {Wiley},
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}
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@Article{Schluns2004,
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author = {Kimberly S. Schluns and Kimberly D. Klonowski and Leo Lefrancois},
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journal = {Blood},
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title = {Transregulation of memory {CD}8 T-cell proliferation by {IL}-15R$\upalpha$+ bone marrow{\textendash}derived cells},
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year = {2004},
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month = {feb},
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number = {3},
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pages = {988--994},
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volume = {103},
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doi = {10.1182/blood-2003-08-2814},
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publisher = {American Society of Hematology},
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}
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@Article{Burkett2003,
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author = {P. R. Burkett and R. Koka and M. Chien and S. Chai and F. Chan and A. Ma and D. L. Boone},
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journal = {Proceedings of the National Academy of Sciences},
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title = {{IL}-15R~ expression on {CD}8+ T cells is dispensable for T cell memory},
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year = {2003},
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month = {apr},
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number = {8},
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pages = {4724--4729},
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volume = {100},
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doi = {10.1073/pnas.0737048100},
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publisher = {Proceedings of the National Academy of Sciences},
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}
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@Article{Olsen2007,
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author = {Shaun K. Olsen and Naruhisa Ota and Seiichiro Kishishita and Mutsuko Kukimoto-Niino and Kazutaka Murayama and Hidemi Uchiyama and Mitsutoshi Toyama and Takaho Terada and Mikako Shirouzu and Osami Kanagawa and Shigeyuki Yokoyama},
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journal = {Journal of Biological Chemistry},
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title = {Crystal Structure of the Interleukin-15$\cdotp$Interleukin-15 Receptor $\upalpha$ Complex},
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year = {2007},
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month = {dec},
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number = {51},
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pages = {37191--37204},
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volume = {282},
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doi = {10.1074/jbc.m706150200},
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publisher = {Elsevier {BV}},
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}
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@Article{Budagian2004,
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author = {Vadim Budagian and Elena Bulanova and Zane Orinska and Andreas Ludwig and Stefan Rose-John and Paul Saftig and Ernest C. Borden and Silvia Bulfone-Paus},
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journal = {Journal of Biological Chemistry},
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title = {Natural Soluble Interleukin-15R$\upalpha$ Is Generated by Cleavage That Involves the Tumor Necrosis Factor-$\upalpha$-converting Enzyme ({TACE}/{ADAM}17)},
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year = {2004},
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month = {sep},
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number = {39},
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pages = {40368--40375},
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volume = {279},
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doi = {10.1074/jbc.m404125200},
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publisher = {Elsevier {BV}},
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}
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@Comment{jabref-meta: databaseType:bibtex;}
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@Comment{jabref-meta: grouping:
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@ -840,47 +840,50 @@ stimulated in the presence of collagen I\cite{Boisvert2007}.
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memory T cells. Its role in the work of this dissertation is the subject of
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further exploration in \cref{aim2b}.
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T cell activation and proliferation is primarily driven through \il{2}, which is
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secreted by activated T cells themselves and functions in a paracrine and
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autocrine manner (). However, \il{15} is functionally similar in that it shares
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almost the same pathway as \il{2} (). In particular, both cytokines share the
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common gamma subchain (CD132) as well as the \il{2} $\upbeta$ receptor (CD122)
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(). The main difference in the heterodimeric receptors for \il{2} and \il{15} is
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the \il{2} $\upalpha$ chain (CD25) and the \il{15} $\upalpha$ chain
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respectively, both of which have high affinity for their respective ligands.
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The \il{2R$\upalpha$} chain itself does not have any signaling capacity, and
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therefore all the signaling resulting from \il{2} is mediated thought the
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$\upbeta$ and $\upgamma$ chains, namely via JAK1 and JAK3 leading to STAT5
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activation consequently T cell activation. \il{15R$\upalpha$} itself has some
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innate signaling capacity, but this is poorly characterized in lymphocytes. Thus
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there is a significant overlap between the functions of \il{2} and \il{15} due
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to their receptors sharing the $\upbeta$ and $\upgamma$ chains in their
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heterodimeric receptors.
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Functionally, mice lacking the gene for either \il{15}\cite{Kennedy2000} or its
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high affinity receptor \il{15R$\upalpha$}\cite{Lodolce1998} are generally
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healthy but show a deficit in memory CD8 T cells, thus underscoring its
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importance in manufacturing high-quality memory T cells for immunotherapies. T
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cells themselves express \il{15} and all of its receptor
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components\cite{MirandaCarus2005}. Additionally, blocking \il{15} itself or
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\il{15R$\upalpha$} \invitro{} has been shown to inhibit homeostatic
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proliferation of resting human T cells\cite{MirandaCarus2005}.
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\il{15} has been puzzling historically because it shares almost the same pathway
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as \il{2} yet has different functions\cite{Stonier2010, Osinalde2014, Giri1994,
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Giri1995}. In particular, both cytokines share the common gamma subchain
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(CD132) as well as the \il{2} $\upbeta$ receptor (CD122). The main difference in
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the heterodimeric receptors for \il{2} and \il{15} is the \il{2} $\upalpha$
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chain (CD25) and the \il{15} $\upalpha$ chain respectively, both of which have
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high affinity for their respective ligands. The \il{2R$\upalpha$} chain itself
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does not have any signaling capacity, and therefore all the signaling resulting
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from \il{2} is mediated thought the $\upbeta$ and $\upgamma$ chains, namely via
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JAK1 and JAK3 leading to STAT5 activation consequently T cell activation.
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\il{15R$\upalpha$} itself has some innate signaling capacity, but this is poorly
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characterized in lymphocytes. Thus there is a significant overlap between the
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functions of \il{2} and \il{15} due to their receptors sharing the $\upbeta$ and
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$\upgamma$ chains in their heterodimeric receptors, and perhaps the main driver
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of their differential functions it the half life of each respective
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receptor\cite{Osinalde2014}.
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Where \il{15} is unique is that many (or possibly most) of its functions derive
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from being membrane-bound to its receptor. Particularly, \il{15R$\upalpha$}
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binds to soluble \il{15} which produces a complex that can transmit signals to
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close neighboring cells (so called \textit{trans} presentation). This has been
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demonstrated in adoptive cell models, where T cells lacking \il{15R$\upalpha$}
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were able to generate memory T cells and proliferate in response to \il{15} when
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given to mice expressing \il{15R$\upalpha$} (). The implication of this
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from being membrane-bound to its receptor\cite{Stonier2010}. Particularly,
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\il{15R$\upalpha$} binds to soluble \il{15} which produces a complex that can
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transmit signals to close neighboring cells (so called \textit{trans}
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presentation). This has been demonstrated in adoptive cell models, where T cells
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lacking \il{15R$\upalpha$} were able to generate memory T cells and proliferate
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only when other cells were present which expressed
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\il{15R$\upalpha$}\cite{Burkett2003, Schluns2004}. The implication of this
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mechanism is that cells expression \il{15R$\upalpha$} either need to express
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\il{15} themselves or be near other cells expressing \il{15}, and that they need
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to be in close proximity to other cells expressing the $\upbeta$ and $\upgamma$
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chains to receive the signal. In addition to \textit{trans} presentation,
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\il{15} may also work in a \textit{cis} manner, where \il{15R$\upalpha$}/\il{15}
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complexes may bind to the $\upbeta$ and $\upgamma$ chains on the same cell,
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assuming all receptors are expressed and soluble \il{15} is available ().
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Finally, \il{15R$\upalpha$} itself can exist in a soluble form, which can bind
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to \il{15} and signal to cells which are not adjacent to the source independent
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of the \textit{cis/trans} mechanisms already described ().
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Functionally, mice lacking the gene for either \il{15} or its
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high affinity receptor \il{15R$\upalpha$} are generally healthy but show a
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deficit in memory CD8 T cells as well as NK cells and NKT cells. T cells
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themselves express \il{15} and all three of its receptor components ().
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Additionally, blocking \il{15} itself or \il{15R$\upalpha$} \invitro{} has been
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shown to inhibit homeostatic proliferation of resting human T cells ().
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\il{15} themselves or be near other cells expressing \il{15}, and other cells in
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proximity require the $\upbeta$ and $\upgamma$ chains to receive the signal. In
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addition to \textit{trans} presentation, \il{15} may also work in a \textit{cis}
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manner, where \il{15R$\upalpha$}/\il{15} complexes may bind to the $\upbeta$ and
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$\upgamma$ chains on the same cell, assuming all receptors are expressed and
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soluble \il{15} is available\cite{Olsen2007}. Finally, \il{15R$\upalpha$} itself can exist in
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a soluble form, which can bind to \il{15} and signal to cells which are not
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adjacent to the source independent of the \textit{cis/trans} mechanisms already
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described\cite{Budagian2004}.
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\subsection*{overview of design of experiments}
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