ADD background on IL15
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@ -78,6 +78,7 @@
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\newacronym{all}{ALL}{acute lymphoblastic leukemia}
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\newacronym{all}{ALL}{acute lymphoblastic leukemia}
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\newacronym{pdms}{PDMS}{polydimethylsiloxane}
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\newacronym{pdms}{PDMS}{polydimethylsiloxane}
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\newacronym{dc}{DC}{dendritic cell}
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\newacronym{dc}{DC}{dendritic cell}
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\newacronym{il}{IL}{interleukin}
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\newacronym{il2}{IL2}{interleukin 2}
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\newacronym{il2}{IL2}{interleukin 2}
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\newacronym{il15}{IL15}{interleukin 15}
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\newacronym{il15}{IL15}{interleukin 15}
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\newacronym{il15r}{IL15R}{interleukin 15 receptor}
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\newacronym{il15r}{IL15R}{interleukin 15 receptor}
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@ -218,6 +219,9 @@
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\newcommand{\ptcar}{\gls{car}+}
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\newcommand{\ptcar}{\gls{car}+}
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\newcommand{\ptcarp}{\ptcar~\si{\percent}}
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\newcommand{\ptcarp}{\ptcar~\si{\percent}}
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% so I don't need to worry about abbreviating all the different interleukins
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\newcommand{\il}[1]{\gls{il}-#1}
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% DOE responses I don't feel like typing ad-nauseam
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% DOE responses I don't feel like typing ad-nauseam
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\newcommand{\pilII}{\gls{il2} concentration}
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\newcommand{\pilII}{\gls{il2} concentration}
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\newcommand{\pdms}{\gls{dms} concentration}
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\newcommand{\pdms}{\gls{dms} concentration}
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@ -667,6 +671,54 @@ stimulated in the presence of collagen I\cite{Boisvert2007}.
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% with fibronectin and has been shown to lead to higher IL2 production (Iwata et
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% with fibronectin and has been shown to lead to higher IL2 production (Iwata et
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% al 2000).
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% al 2000).
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\subsection*{the role of IL15 in memory T cell proliferation}
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\il{15} is a cytokine that is involved with the proliferation and homeostasis of
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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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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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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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\subsection*{strategies to optimize cell manufacturing}
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\subsection*{strategies to optimize cell manufacturing}
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The \gls{dms} system has a number of parameters that can be optimized, and a
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The \gls{dms} system has a number of parameters that can be optimized, and a
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