ADD beefier background section on integrin pathways

tex/references.bib

@@ -1400,6 +1400,96 @@ CONCLUSIONS: We developed a simplified, semi-closed system for the initial selec
   publisher = {Springer Science and Business Media {LLC}},
 }
 
+@Article{Dustin2001,
+  author    = {Michael L Dustin and Antonin R de Fougerolles},
+  journal   = {Current Opinion in Immunology},
+  title     = {Reprograming T cells: the role of extracellular matrix in coordination of T cell activation and migration},
+  year      = {2001},
+  month     = {jun},
+  number    = {3},
+  pages     = {286--290},
+  volume    = {13},
+  doi       = {10.1016/s0952-7915(00)00217-x},
+  publisher = {Elsevier {BV}},
+}
+
+@Article{Ebnet1996,
+  author    = {Klaus Ebnet and Eric P. Kaldjian and Arthur O. Anderson and Stephen Shaw},
+  journal   = {Annual Review of Immunology},
+  title     = {{ORCHESTRATED} {INFORMATION} {TRANSFER} {UNDERLYING} {LEUKOCYTE} {ENDOTHELIAL} {INTERACTIONS}},
+  year      = {1996},
+  month     = {apr},
+  number    = {1},
+  pages     = {155--177},
+  volume    = {14},
+  doi       = {10.1146/annurev.immunol.14.1.155},
+  publisher = {Annual Reviews},
+}
+
+@Article{Gunzer2000,
+  author    = {Matthias Gunzer and Angelika Schäfer and Stefan Borgmann and Stephan Grabbe and Kurt S. Zänker and Eva-Bettina Bröcker and Eckhart Kämpgen and Peter Friedl},
+  journal   = {Immunity},
+  title     = {Antigen Presentation in Extracellular Matrix},
+  year      = {2000},
+  month     = {sep},
+  number    = {3},
+  pages     = {323--332},
+  volume    = {13},
+  doi       = {10.1016/s1074-7613(00)00032-7},
+  publisher = {Elsevier {BV}},
+}
+
+@Article{Aoudjit2000,
+  author          = {Aoudjit, F. and Vuori, K.},
+  journal         = {Blood},
+  title           = {Engagement of the alpha2beta1 integrin inhibits Fas ligand expression and activation-induced cell death in T cells in a focal adhesion kinase-dependent manner.},
+  year            = {2000},
+  issn            = {0006-4971},
+  month           = mar,
+  pages           = {2044--2051},
+  volume          = {95},
+  abstract        = {T-cell receptor (TCR)-mediated apoptosis, also known as activation-induced cell death (AICD), plays an important role in the control of immune response and in the development of T-cell repertoire. Mechanistically, AICD has been largely attributed to the interaction of Fas ligand (Fas-L) with its cell surface receptor Fas in activated T cells. Signal transduction mediated by the integrin family of cell adhesion receptors has been previously shown to modulate apoptosis in a number of different cell types; in T cells, integrin signaling is known to be important in cellular response to antigenic challenge by providing a co-stimulatory signal for TCR. In this study we demonstrate that signaling via the collagen receptor alpha2beta1 integrin specifically inhibits AICD by inhibiting Fas-L expression in activated Jurkat T cells. Engagement of the alpha2beta1 integrin with monoclonal antibodies or with type I collagen, a cognate ligand for alpha2beta1, reduced anti-CD3 and PMA/ionomycin-induced cell death by 30% and 40%, respectively, and the expression of Fas-L mRNA by 50%. Further studies indicated that the alpha2beta1-mediated inhibition of AICD and Fas-L expression required the focal adhesion kinase FAK, a known component in the integrin signaling pathways. These results suggest a role for the alpha2beta1 integrin in the control of homeostasis of immune response and T-cell development. (Blood. 2000;95:2044-2051)},
+  chemicals       = {CD3 Complex, Cell Adhesion Molecules, FASLG protein, human, Fas Ligand Protein, Integrins, Ionophores, Membrane Glycoproteins, Protein Synthesis Inhibitors, RNA, Messenger, Receptors, Collagen, Ionomycin, Collagen, Cycloheximide, FAK-related nonkinase, Protein-Tyrosine Kinases, Focal Adhesion Kinase 1, Focal Adhesion Protein-Tyrosine Kinases, PTK2 protein, human, Tetradecanoylphorbol Acetate},
+  citation-subset = {AIM, IM},
+  completed       = {2000-04-07},
+  country         = {United States},
+  issn-linking    = {0006-4971},
+  issue           = {6},
+  keywords        = {Apoptosis; CD3 Complex, metabolism; Cell Adhesion Molecules, metabolism; Cell Death; Collagen, metabolism; Cycloheximide, pharmacology; DNA Fragmentation; Fas Ligand Protein; Flow Cytometry; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Humans; Integrins, metabolism; Ionomycin, pharmacology; Ionophores, pharmacology; Jurkat Cells; Membrane Glycoproteins, metabolism; Plasmids; Protein Synthesis Inhibitors, pharmacology; Protein-Tyrosine Kinases, metabolism; RNA, Messenger, metabolism; Receptors, Collagen; Signal Transduction; T-Lymphocytes, metabolism, pathology; Tetradecanoylphorbol Acetate, pharmacology; Transfection},
+  nlm-id          = {7603509},
+  owner           = {NLM},
+  pii             = {S0006-4971(20)66967-1},
+  pmid            = {10706873},
+  pubmodel        = {Print},
+  pubstate        = {ppublish},
+  revised         = {2021-02-16},
+}
+
+@Article{Hemler1990,
+  author          = {Hemler, M. E.},
+  journal         = {Annual review of immunology},
+  title           = {VLA proteins in the integrin family: structures, functions, and their role on leukocytes.},
+  year            = {1990},
+  issn            = {0732-0582},
+  pages           = {365--400},
+  volume          = {8},
+  nasa            = {90262672},
+  chemicals       = {Integrins, Receptors, Very Late Antigen},
+  citation-subset = {IM, S},
+  completed       = {1990-07-02},
+  country         = {United States},
+  doi             = {10.1146/annurev.iy.08.040190.002053},
+  issn-linking    = {0732-0582},
+  keywords        = {Animals; Cell Adhesion; Extracellular Matrix, physiology; Humans; Integrins, biosynthesis, physiology; Leukocytes, physiology; Receptors, Very Late Antigen, biosynthesis, physiology; Structure-Activity Relationship},
+  nlm-id          = {8309206},
+  owner           = {NLM},
+  pmid            = {2188667},
+  pubmodel        = {Print},
+  pubstate        = {ppublish},
+  references      = {212},
+  revised         = {2021-01-02},
+}
+
 @Comment{jabref-meta: databaseType:bibtex;}
 
 @Comment{jabref-meta: grouping:

tex/thesis.tex

@@ -586,10 +586,12 @@ under close cell-cell contact via \glspl{apc} such as \glspl{dc}, which present
 peptide-\glspl{mhc} to T cells as well as a variety of other costimulatory
 signals. These close quarters allow for efficient autocrine/paracrine signaling
 among the expanding T cells, which secrete gls{il2} and other cytokines to
-assist their own growth. Additionally, the lymphoid tissues are comprised of
-\gls{ecm} components such as collagen, which provide signals to upregulate
-proliferation, cytokine production, and pro-survival pathways\cite{Gendron2003,
-  Ohtani2008, Boisvert2007, Ben-Horin2004}.
+assist their own growth.
+
+% Additionally, the lymphoid tissues are comprised of
+% \gls{ecm} components such as collagen, which provide signals to upregulate
+% proliferation, cytokine production, and pro-survival pathways\cite{Gendron2003,
+%   Ohtani2008, Boisvert2007, Ben-Horin2004}.
 
 A variety of solutions have been proposed to make the T cell expansion process
 more physiological. One strategy is to use modified feeder cell cultures to
@@ -629,6 +631,42 @@ cells to interact with the \glspl{mab} relative to beads; this may better
 emulate the large contact surface area that occurs between T cells and
 \glspl{dc}.
 
+\subsection*{integrins and T cell signaling}
+
+Because the microcarriers used in this work are derived from collagen, one key
+question is how these collagen domains may interact with the T cells during
+culture. This question is further explored in \cref{aim2b}.
+
+T cells naturally expand in the lymph nodes which have an \gls{ecm} composed of
+collagen\cite{Dustin2001, Ebnet1996, Ohtani2008}. Despite this, T cells don't
+interact with collagen fibers in the lymph node as the collagen fibers are
+sheathed with stromal fibroblasts\cite{Dustin2001, Ebnet1996}. However, the
+\gls{ecm} of peripheral tissues is dense with exposed collagen fibers are
+available to interact with T cells. Furthermore, T cells have been shown
+\invitro{} to crawl along collagen fibers in the presence of \glspl{apc},
+facilitating short encounters with \glspl{apc}\cite{Gunzer2000}. While this may
+not be ideal \invivo{} due to the lack of cumulative signal received by
+\glspl{apc}\cite{Dustin2001}, it may be advantageous to include collagen domains
+\invitro{} as the mode of activation is not specific to any given clone.
+
+The major surface receptors for collagen are \gls{a2b1} and
+\gls{a2b2}\cite{Dustin2001, Hemler1990}. These receptors are not expressed on
+naive T cells and thus presence and stimulation of collagen alone is not
+sufficient to cause activation or expansion of T cells\cite{Hemler1990}. These
+receptors have been shown to lead to a number of functions that may be useful in
+the context of T cell expansion. First, they have been shown to act in a
+costimulatory manner which leads to increased proliferation\cite{Rao2000}.
+Furthermore, \gls{a2b1} and \gls{a2b2} have been shown to protect Jurkat cells
+against Fas-mediated apoptosis in the presence of collagen I\cite{Aoudjit2000,
+  Gendron2003}. Finally, these receptors have been shown to increase \gls{ifng}
+production \invitro{} when T cells derived from human \glspl{pbmc} are
+stimulated in the presence of collagen I\cite{Boisvert2007}.
+
+% TODO there are other receptors I could name here that were not explored
+% Other integrins that interact with the environment include a4b1, which interacts
+% with fibronectin and has been shown to lead to higher IL2 production (Iwata et
+% al 2000).
+
 \subsection*{strategies to optimize cell manufacturing}
 
 The \gls{dms} system has a number of parameters that can be optimized, and a