From 1ce4b6bd01796c16e4204f29eaca3c88812a1b13 Mon Sep 17 00:00:00 2001
From: ndwarshuis <ndwar@yavin4.ch>
Date: Sun, 1 Aug 2021 16:43:29 -0400
Subject: [PATCH] ADD background on IL15

---
 tex/thesis.tex | 52 ++++++++++++++++++++++++++++++++++++++++++++++++++
 1 file changed, 52 insertions(+)

diff --git a/tex/thesis.tex b/tex/thesis.tex
index 435fdb6..e0049c5 100644
--- a/tex/thesis.tex
+++ b/tex/thesis.tex
@@ -78,6 +78,7 @@
 \newacronym{all}{ALL}{acute lymphoblastic leukemia}
 \newacronym{pdms}{PDMS}{polydimethylsiloxane}
 \newacronym{dc}{DC}{dendritic cell}
+\newacronym{il}{IL}{interleukin}
 \newacronym{il2}{IL2}{interleukin 2}
 \newacronym{il15}{IL15}{interleukin 15}
 \newacronym{il15r}{IL15R}{interleukin 15 receptor}
@@ -218,6 +219,9 @@
 \newcommand{\ptcar}{\gls{car}+}
 \newcommand{\ptcarp}{\ptcar~\si{\percent}}
 
+% so I don't need to worry about abbreviating all the different interleukins
+\newcommand{\il}[1]{\gls{il}-#1}
+
 % DOE responses I don't feel like typing ad-nauseam
 \newcommand{\pilII}{\gls{il2} concentration}
 \newcommand{\pdms}{\gls{dms} concentration}
@@ -667,6 +671,54 @@ stimulated in the presence of collagen I\cite{Boisvert2007}.
 % with fibronectin and has been shown to lead to higher IL2 production (Iwata et
 % al 2000).
 
+\subsection*{the role of IL15 in memory T cell proliferation}
+
+\il{15} is a cytokine that is involved with the proliferation and homeostasis of
+memory T cells. Its role in the work of this dissertation is the subject of
+further exploration in \cref{aim2b}.
+
+T cell activation and proliferation is primarily driven through \il{2}, which is
+secreted by activated T cells themselves and functions in a paracrine and
+autocrine manner (). However, \il{15} is functionally similar in that it shares
+almost the same pathway as \il{2} (). In particular, both cytokines share the
+common gamma subchain (CD132) as well as the \il{2} $\upbeta$ receptor (CD122)
+(). The main difference in the heterodimeric receptors for \il{2} and \il{15} is
+the \il{2} $\upalpha$ chain (CD25) and the \il{15} $\upalpha$ chain
+respectively, both of which have high affinity for their respective ligands.
+The \il{2R$\upalpha$} chain itself does not have any signaling capacity, and
+therefore all the signaling resulting from \il{2} is mediated thought the
+$\upbeta$ and $\upgamma$ chains, namely via JAK1 and JAK3 leading to STAT5
+activation consequently T cell activation. \il{15R$\upalpha$} itself has some
+innate signaling capacity, but this is poorly characterized in lymphocytes. Thus
+there is a significant overlap between the functions of \il{2} and \il{15} due
+to their receptors sharing the $\upbeta$ and $\upgamma$ chains in their
+heterodimeric receptors.
+
+Where \il{15} is unique is that many (or possibly most) of its functions derive
+from being membrane-bound to its receptor. Particularly, \il{15R$\upalpha$}
+binds to soluble \il{15} which produces a complex that can transmit signals to
+close neighboring cells (so called \textit{trans} presentation). This has been
+demonstrated in adoptive cell models, where T cells lacking \il{15R$\upalpha$}
+were able to generate memory T cells and proliferate in response to \il{15} when
+given to mice expressing \il{15R$\upalpha$} (). The implication of this
+mechanism is that cells expression \il{15R$\upalpha$} either need to express
+\il{15} themselves or be near other cells expressing \il{15}, and that they need
+to be in close proximity to other cells expressing the $\upbeta$ and $\upgamma$
+chains to receive the signal. In addition to \textit{trans} presentation,
+\il{15} may also work in a \textit{cis} manner, where \il{15R$\upalpha$}/\il{15}
+complexes may bind to the $\upbeta$ and $\upgamma$ chains on the same cell,
+assuming all receptors are expressed and soluble \il{15} is available ().
+Finally, \il{15R$\upalpha$} itself can exist in a soluble form, which can bind
+to \il{15} and signal to cells which are not adjacent to the source independent
+of the \textit{cis/trans} mechanisms already described ().
+
+Functionally, mice lacking the gene for either \il{15} or its
+high affinity receptor \il{15R$\upalpha$} are generally healthy but show a
+deficit in memory CD8 T cells as well as NK cells and NKT cells. T cells
+themselves express \il{15} and all three of its receptor components ().
+Additionally, blocking \il{15} itself or \il{15R$\upalpha$} \invitro{} has been
+shown to inhibit homeostatic proliferation of resting human T cells ().
+
 \subsection*{strategies to optimize cell manufacturing}
 
 The \gls{dms} system has a number of parameters that can be optimized, and a