ENH tighten up the mouse discussion
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@ -2544,6 +2544,45 @@ CONCLUSIONS: We developed a simplified, semi-closed system for the initial selec
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revised = {2008-07-28},
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revised = {2008-07-28},
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}
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}
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@Article{Lozza2008,
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author = {Laura Lozza and Laura Rivino and Greta Guarda and David Jarrossay and Andrea Rinaldi and Francesco Bertoni and Federica Sallusto and Antonio Lanzavecchia and Jens Geginat},
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journal = {European Journal of Immunology},
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title = {The strength of T cell stimulation determines {IL}-7 responsiveness, secondary expansion, and lineage commitment of primed human {CD}4+{IL}-7Rhi T cells},
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year = {2008},
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month = {jan},
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number = {1},
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pages = {30--39},
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volume = {38},
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doi = {10.1002/eji.200737852},
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publisher = {Wiley},
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}
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@Article{Lanzavecchia2005,
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author = {Antonio Lanzavecchia and Federica Sallusto},
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journal = {Current Opinion in Immunology},
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title = {Understanding the generation and function of memory T cell subsets},
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year = {2005},
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month = {jun},
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number = {3},
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pages = {326--332},
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volume = {17},
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doi = {10.1016/j.coi.2005.04.010},
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publisher = {Elsevier {BV}},
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}
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@Article{Corse2011,
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author = {Emily Corse and Rachel A. Gottschalk and James P. Allison},
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journal = {The Journal of Immunology},
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title = {Strength of {TCR}{\textendash}Peptide/{MHC} Interactions and In Vivo T Cell Responses},
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year = {2011},
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month = {apr},
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number = {9},
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pages = {5039--5045},
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volume = {186},
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doi = {10.4049/jimmunol.1003650},
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publisher = {The American Association of Immunologists},
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}
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@Comment{jabref-meta: databaseType:bibtex;}
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@Comment{jabref-meta: databaseType:bibtex;}
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@Comment{jabref-meta: grouping:
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@Comment{jabref-meta: grouping:
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@ -2465,6 +2465,9 @@ however, to our knowledge this is the first system that specifically drives
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naïve/memory and CD4+ T cell formation in a scalable, potentially
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naïve/memory and CD4+ T cell formation in a scalable, potentially
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bioreactor-compatible manufacturing process.
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bioreactor-compatible manufacturing process.
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% DISCUSSION assuage krish by showing that in the isotype control fig that IL2
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% doesn't activation T cells: https://www.jimmunol.org/content/jimmunol/191/12/5822.full.pdf
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Memory and naïve T cells have been shown to be important clinically. Compared to
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Memory and naïve T cells have been shown to be important clinically. Compared to
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effectors, they have a higher proliferative capacity and are able to engraft for
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effectors, they have a higher proliferative capacity and are able to engraft for
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months; thus they are able to provide long-term immunity with smaller
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months; thus they are able to provide long-term immunity with smaller
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@ -4148,8 +4151,6 @@ other groups in regard to the final tumor burden.
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\section{discussion}
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\section{discussion}
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% FIGURE add CD45RA to this to rule out one of the alternative possibilities
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% explaining this data
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\begin{figure*}[ht!]
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\begin{figure*}[ht!]
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\begingroup
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\begingroup
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@ -4163,7 +4164,8 @@ other groups in regard to the final tumor burden.
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\subcap{fig:mouse_summary_1}{the first mouse experiment} and
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\subcap{fig:mouse_summary_1}{the first mouse experiment} and
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\subcap{fig:mouse_summary_2}{the second mouse experiment}. The y axis
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\subcap{fig:mouse_summary_2}{the second mouse experiment}. The y axis
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maximum is set to the maximum number of cells injected between both
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maximum is set to the maximum number of cells injected between both
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experiments (\num{1.25e6}).
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experiments (\num{1.25e6}). Note that the \gls{car} was quantified using a
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separate panel than the rest of the markers.
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}
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}
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\label{fig:mouse_summary}
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\label{fig:mouse_summary}
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\end{figure*}
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\end{figure*}
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@ -4180,32 +4182,32 @@ tumor burden was higher than DMS groups across all the total T cell doses tested
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here. More interestingly, when only CAR-expressing T cell doses between bead and
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here. More interestingly, when only CAR-expressing T cell doses between bead and
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DMS groups were compared, DMS group had significantly higher survival effects
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DMS groups were compared, DMS group had significantly higher survival effects
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over similar or higher CAR expression T cell doses from bead group. All these
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over similar or higher CAR expression T cell doses from bead group. All these
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results suggest that the higher proportion of memory T cells in DMS groups
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results suggest that the T cells in DMS groups (compared to bead group) resulted
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(compared to bead group) resulted in highly effective CAR-T cells that can
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in highly effective CAR-T cells that can efficiently kill tumor cells.
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efficiently kill tumor cells as recently reported in
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literature\cite{Fraietta2018, Sommermeyer2015}.
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% DISCUSSION cite a bunch of data saying memory and CD4 T cells are better in
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% mice
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When comparing the total number of T cells of different phenotypes, we observed
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When comparing the total number of T cells of different phenotypes, we observed
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that when comparing low-dose \gls{dms} group to the mid- bead groups (which had
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that when comparing low-dose \gls{dms} group to the mid- bead groups (which had
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similar numbers of \gls{car} T cells), the number of \ptmem{} T cells injected
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similar numbers of \gls{car} T cells), the number of \ptmem{} (both with and
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was much lower in the \gls{dms} group (\cref{fig:mouse_summary_1}). This could
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without CD45RA) T cells injected was much lower in the \gls{dms} group
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mean several things. First, the \ptmem{} phenotype may have nothing to do with
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(\cref{fig:mouse_summary_1}). This could mean several things. First, the
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the results seen here, at least in this model. Second, the distribution of
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\ptmem{} phenotype may have nothing to do with the results seen here, at least
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\gls{car} T cells across different subtypes of T cells was different between the
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in this model. While this may have been the case in our hands, this would
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\gls{dms} and bead groups (with possibly higher correlation of \gls{car}
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contradict previous evidence suggesting that \gls{tn} and \gls{tcm} cells work
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expression and the \ptmem{} phenotype). Third, the \ptmem{} phenotype may not be
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better in almost the same model (the only difference being Raji cells in place
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precise enough, and the functional `memory' phenotype is a subset of \ptmem{}
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of Nalm-6 cells, both of which express CD19)\cite{Sommermeyer2015}. Second, the
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which may be higher in the \gls{dms} group and explains the discrepancy between
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distribution of \gls{car} T cells across different subtypes of T cells was
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the two methods.
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different between the \gls{dms} and bead groups (with possibly higher
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correlation of \gls{car} expression and the \ptmem{} phenotype). It is hard to
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assess this without strong assumptions as the \gls{car} was quantified using a
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separate flow panel relative to the other markers.
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% DISCUSSION cite why CD4 or CD8 matters in this model
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We can also make a similar observation for the number of \pth{} T cells injected
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We can also make a similar observation for the number of \pth{} T cells injected
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(\cref{fig:mouse_summary_1}). In this case, either the \pth{} phenotype doesn't
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(\cref{fig:mouse_summary_1}). In this case, either the \pth{} phenotype doesn't
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matter in this model (or the \ptk{} population matters much more), or the
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matter in this model (or the \ptk{} population matters much more), or the
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distribution of \gls{car} is different between CD4 and CD8 T cells in a manner
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distribution of \gls{car} is different between CD4 and CD8 T cells in a manner
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that favors the \gls{dms} group.
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that favors the \gls{dms} group. While in a glioblastoma model and not a B-cell
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\gls{all} model, previous groups have shown that \pthp{} T cells are important
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for response\cite{Wang2018}.
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When testing \gls{car} T cells at earlier timepoints relative to day 14 as used
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When testing \gls{car} T cells at earlier timepoints relative to day 14 as used
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in the first \invivo{} experiment, we noted that none of the \gls{car}
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in the first \invivo{} experiment, we noted that none of the \gls{car}
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@ -4221,10 +4223,11 @@ to perform better at day 6 as it held off the tumor longer, and also slowed the
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tumor progression relative to the bead group at day 14
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tumor progression relative to the bead group at day 14
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(\cref{fig:mouse_timecourse_ivis_plots}).
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(\cref{fig:mouse_timecourse_ivis_plots}).
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Taken together, these data suggest that on average, the \gls{dms} platform
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Taken together, these data suggest that the \gls{dms} platform produces T cells
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produces T cells that have an advantage \invivo{} over beads. While we may not
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that have an advantage \invivo{} over beads. While we may not know the exact
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know the exact mechanism, our data suggests that the responses are
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mechanism, our data suggests that the responses are unsurprisingly influenced by
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unsurprisingly influenced by the \ptcarp{} of the final product.
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the \ptcarp{} of the final product. Followup experiments would need to be
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performed to determine the precise phenotype responsible for these responses.
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\chapter{conclusions and future work}\label{conclusions}
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\chapter{conclusions and future work}\label{conclusions}
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@ -4287,13 +4290,13 @@ to control and optimize the \gls{dms} system. We determined that altering the
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\gls{dms} concentration temporally has profound effects on the phenotype and
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\gls{dms} concentration temporally has profound effects on the phenotype and
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expansion rate. This agrees with other data we obtained in \cref{aim2a} and with
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expansion rate. This agrees with other data we obtained in \cref{aim2a} and with
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what others have generally reported about signal strength and T cell
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what others have generally reported about signal strength and T cell
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differentiation\cite{Gattinoni2012}. We did not find any mechanistic
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differentiation\cite{Gattinoni2012, Lozza2008, Lanzavecchia2005, Corse2011}. We
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relationship between either integrin signaling or \gls{il15} signaling. In the
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did not find any mechanistic relationship between either integrin signaling or
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case of the former, it may be more likely that the \glspl{dms} surfaces are
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\gls{il15} signaling. In the case of the former, it may be more likely that the
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saturated to the point of sterically hindering any integrin interactions with
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\glspl{dms} surfaces are saturated to the point of sterically hindering any
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the collagen surface. In the case of \gls{il15} more experiments likely need to
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integrin interactions with the collagen surface. In the case of \gls{il15} more
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be done in order to plausibly rule out this mechanism and/or determine if it is
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experiments likely need to be done in order to plausibly rule out this mechanism
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involved at all.
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and/or determine if it is involved at all.
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% TODO make this tighter and cite paper showing that this makes at least some
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% TODO make this tighter and cite paper showing that this makes at least some
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% sense
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% sense
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