ndwarshuis
/
phd_thesis
1
0
Fork 0
Code Issues Pull Requests Packages Projects Releases Wiki Activity

ADD background on IL15

This commit is contained in:
Nathan Dwarshuis 2021-08-01 16:43:29 -04:00
parent adb80cb94e
commit 1ce4b6bd01
1 changed files with 52 additions and 0 deletions
Show Stats Download Patch File Download Diff File Expand all files Collapse all files

52
tex/thesis.tex
View File

@ -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