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@@ -739,10 +739,13 @@ literal "false"
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Like any adaptive immune response, graft rejection generally occurs via
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Like any adaptive immune response, graft rejection generally occurs via
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- two broad mechanisms: cellular immunity, in which CD8+ T-cells recognizing
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- graft-specific antigens induce apoptosis in the graft cells; and humoral
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- immunity, in which B-cells produce antibodies that bind to graft proteins
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- and direct an immune response against the graft
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+ two broad mechanisms: cellular immunity, in which CD8
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+\begin_inset Formula $^{+}$
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+\end_inset
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+
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+ T-cells recognizing graft-specific antigens induce apoptosis in the graft
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+ cells; and humoral immunity, in which B-cells produce antibodies that bind
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+ to graft proteins and direct an immune response against the graft
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\begin_inset CommandInset citation
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\begin_inset CommandInset citation
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LatexCommand cite
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LatexCommand cite
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key "Murphy2012"
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key "Murphy2012"
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@@ -752,8 +755,11 @@ literal "false"
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In either case, rejection shows most of the typical hallmarks of an adaptive
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In either case, rejection shows most of the typical hallmarks of an adaptive
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- immune response, in particular mediation by CD4+ T-cells and formation
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- of immune memory.
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+ immune response, in particular mediation by CD4
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+\begin_inset Formula $^{+}$
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+\end_inset
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+
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+ T-cells and formation of immune memory.
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\end_layout
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\end_layout
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\begin_layout Subsection
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\begin_layout Subsection
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@@ -1073,7 +1079,11 @@ RNA-seq
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\end_layout
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\end_layout
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\begin_layout Subsection
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\begin_layout Subsection
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-Investigate dynamics of histone marks in CD4 T-cell activation and memory
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+Investigate dynamics of histone marks in CD4
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+\begin_inset Formula $^{+}$
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+\end_inset
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+
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+ T-cell activation and memory
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\end_layout
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\end_layout
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\begin_layout Standard
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\begin_layout Standard
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@@ -2479,7 +2489,11 @@ PCA
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\begin_layout Chapter
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\begin_layout Chapter
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Reproducible genome-wide epigenetic analysis of H3K4 and H3K27 methylation
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Reproducible genome-wide epigenetic analysis of H3K4 and H3K27 methylation
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- in naïve and memory CD4 T-cell activation
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+ in naïve and memory CD4
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+\begin_inset Formula $^{+}$
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+\end_inset
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+
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+ T-cell activation
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\end_layout
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\end_layout
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\begin_layout Standard
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\begin_layout Standard
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@@ -2525,60 +2539,40 @@ Approach
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\end_layout
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\end_layout
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\begin_layout Standard
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\begin_layout Standard
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-\begin_inset Flex TODO Note (inline)
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-status open
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-
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-\begin_layout Plain Layout
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-Check on the exact correct way to write
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-\begin_inset Quotes eld
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-\end_inset
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-
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-CD4 T-cell
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-\begin_inset Quotes erd
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+CD4
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+\begin_inset Formula $^{+}$
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\end_inset
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\end_inset
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-.
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- I think there might be a plus sign somewhere in there now? Also, maybe
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- figure out a reasonable way to abbreviate
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-\begin_inset Quotes eld
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-\end_inset
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+ T-cells are central to all adaptive immune responses, as well as immune
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+ memory
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+\begin_inset CommandInset citation
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+LatexCommand cite
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+key "Murphy2012"
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+literal "false"
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-naïve CD4 T-cells
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-\begin_inset Quotes erd
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\end_inset
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\end_inset
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- and
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-\begin_inset Quotes eld
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+.
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+ After an infection is cleared, a subset of the naïve CD4
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+\begin_inset Formula $^{+}$
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\end_inset
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\end_inset
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-memory CD4 T-cells
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-\begin_inset Quotes erd
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+ T-cells that responded to that infection differentiate into memory CD4
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+\begin_inset Formula $^{+}$
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\end_inset
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\end_inset
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-.
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-\end_layout
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-
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+ T-cells, which are responsible for responding to the same pathogen in the
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+ future.
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+ Memory CD4
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+\begin_inset Formula $^{+}$
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\end_inset
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\end_inset
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-
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-\end_layout
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-
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-\begin_layout Standard
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-CD4 T-cells are central to all adaptive immune responses, as well as immune
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- memory
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-\begin_inset CommandInset citation
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-LatexCommand cite
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-key "Murphy2012"
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-literal "false"
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-
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+ T-cells are functionally distinct, able to respond to an infection more
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+ quickly and without the co-stimulation required by naïve CD4
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+\begin_inset Formula $^{+}$
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\end_inset
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\end_inset
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-.
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- After an infection is cleared, a subset of the naïve CD4 T-cells that responded
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- to that infection differentiate into memory CD4 T-cells, which are responsible
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- for responding to the same pathogen in the future.
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- Memory CD4 T-cells are functionally distinct, able to respond to an infection
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- more quickly and without the co-stimulation required by naïve CD4 T-cells.
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+ T-cells.
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However, the molecular mechanisms underlying this functional distinction
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However, the molecular mechanisms underlying this functional distinction
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are not well-understood.
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are not well-understood.
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Epigenetic regulation via histone modification is thought to play an important
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Epigenetic regulation via histone modification is thought to play an important
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@@ -2589,7 +2583,11 @@ literal "false"
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H3K4me2, H3K4me3 and H3K27me3 are three histone marks thought to be major
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H3K4me2, H3K4me3 and H3K27me3 are three histone marks thought to be major
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epigenetic regulators of gene expression.
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epigenetic regulators of gene expression.
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The goal of the present study is to investigate the role of these histone
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The goal of the present study is to investigate the role of these histone
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- marks in CD4 T-cell activation kinetics and memory differentiation.
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+ marks in CD4
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+\begin_inset Formula $^{+}$
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+\end_inset
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+
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+ T-cell activation kinetics and memory differentiation.
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In static snapshots, H3K4me2 and H3K4me3 are often observed in the promoters
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In static snapshots, H3K4me2 and H3K4me3 are often observed in the promoters
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of highly transcribed genes, while H3K27me3 is more often observed in promoters
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of highly transcribed genes, while H3K27me3 is more often observed in promoters
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of inactive genes with little to no transcription occurring.
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of inactive genes with little to no transcription occurring.
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@@ -2617,8 +2615,11 @@ deactivating
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\begin_layout Standard
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\begin_layout Standard
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In order to investigate the relationship between gene expression and these
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In order to investigate the relationship between gene expression and these
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- histone modifications in the context of naïve and memory CD4 T-cell activation,
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- a previously published data set of
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+ histone modifications in the context of naïve and memory CD4
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+\begin_inset Formula $^{+}$
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+\end_inset
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+
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+ T-cell activation, a previously published data set of
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\begin_inset Flex Glossary Term
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\begin_inset Flex Glossary Term
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status open
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status open
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@@ -2640,8 +2641,11 @@ ChIP-seq
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data was re-analyzed using up-to-date methods designed to address the specific
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data was re-analyzed using up-to-date methods designed to address the specific
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analysis challenges posed by this data set.
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analysis challenges posed by this data set.
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- The data set contains naïve and memory CD4 T-cell samples in a time course
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- before and after activation.
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+ The data set contains naïve and memory CD4
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+\begin_inset Formula $^{+}$
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+\end_inset
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+
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+ T-cell samples in a time course before and after activation.
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Like the original analysis, this analysis looks at the dynamics of these
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Like the original analysis, this analysis looks at the dynamics of these
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marks histone marks and compare them to gene expression dynamics at the
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marks histone marks and compare them to gene expression dynamics at the
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same time points during activation, as well as compare them between naïve
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same time points during activation, as well as compare them between naïve
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@@ -2752,8 +2756,16 @@ ChIP-seq
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\end_inset
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\end_inset
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- from CD4 T-cells from 4 donors.
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- From each donor, naïve and memory CD4 T-cells were isolated separately.
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+ from CD4
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+\begin_inset Formula $^{+}$
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+\end_inset
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+
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+ T-cells from 4 donors.
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+ From each donor, naïve and memory CD4
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+\begin_inset Formula $^{+}$
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+\end_inset
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+
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+ T-cells were isolated separately.
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Then cultures of both cells were activated with CD3/CD28 beads, and samples
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Then cultures of both cells were activated with CD3/CD28 beads, and samples
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were taken at 4 time points: Day 0 (pre-activation), Day 1 (early activation),
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were taken at 4 time points: Day 0 (pre-activation), Day 1 (early activation),
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Day 5 (peak activation), and Day 14 (post-activation).
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Day 5 (peak activation), and Day 14 (post-activation).
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@@ -8993,7 +9005,10 @@ LF
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in all 4 data sets, indicating a coordinated pattern of variation shared
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in all 4 data sets, indicating a coordinated pattern of variation shared
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across all histone marks and gene expression.
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across all histone marks and gene expression.
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This, of course, is consistent with the expectation that any naïve CD4
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This, of course, is consistent with the expectation that any naïve CD4
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- T-cells remaining at day 14 should have differentiated into memory cells
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+\begin_inset Formula $^{+}$
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+\end_inset
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+
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+ T-cells remaining at day 14 should have differentiated into memory cells
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by that time, and should therefore have a genomic state similar to memory
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by that time, and should therefore have a genomic state similar to memory
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cells.
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cells.
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This convergence is evidence that these histone marks all play an important
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This convergence is evidence that these histone marks all play an important
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@@ -9138,7 +9153,10 @@ status collapsed
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\begin_layout Plain Layout
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\begin_layout Plain Layout
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Lamere 2016 Figure 8 “Model for the role of H3K4 methylation during CD4
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Lamere 2016 Figure 8 “Model for the role of H3K4 methylation during CD4
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- T-cell activation.
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+\begin_inset Formula $^{+}$
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+\end_inset
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+
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+ T-cell activation.
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\begin_inset Quotes erd
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\begin_inset Quotes erd
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\end_inset
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\end_inset
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@@ -9168,7 +9186,15 @@ literal "false"
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\begin_inset Quotes eld
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\begin_inset Quotes eld
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\end_inset
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\end_inset
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-Model for the role of H3K4 methylation during CD4 T-cell activation.
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+Model for the role of H3K4 methylation during
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+\series default
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+CD4
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+\begin_inset Formula $^{+}$
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+\end_inset
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+
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+
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+\series bold
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+ T-cell activation.
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\begin_inset Quotes erd
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\begin_inset Quotes erd
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\end_inset
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\end_inset
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@@ -9726,7 +9752,11 @@ ChIP-seq
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\end_inset
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\end_inset
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- in CD4 T-cells in Chapter 2 is in many ways a preliminary study that suggests
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+ in CD4
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+\begin_inset Formula $^{+}$
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+\end_inset
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+
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+ T-cells in Chapter 2 is in many ways a preliminary study that suggests
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a multitude of new avenues of investigation.
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a multitude of new avenues of investigation.
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Here we consider a selection of such avenues.
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Here we consider a selection of such avenues.
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\end_layout
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\end_layout
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@@ -10013,10 +10043,14 @@ In this study, a convergence between naïve and memory cells was observed
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However, the current study was not designed with this specific hypothesis
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However, the current study was not designed with this specific hypothesis
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in mind, and it therefore has some deficiencies with regard to testing
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in mind, and it therefore has some deficiencies with regard to testing
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it.
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it.
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- The memory CD4 samples at day 14 do not resemble the memory samples at
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- day 0, indicating that in the specific model of activation used for this
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- experiment, the cells are not guaranteed to return to their original pre-activa
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-tion state, or perhaps this process takes substantially longer than 14 days.
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+ The memory CD4
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+\begin_inset Formula $^{+}$
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+\end_inset
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+
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+ samples at day 14 do not resemble the memory samples at day 0, indicating
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+ that in the specific model of activation used for this experiment, the
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+ cells are not guaranteed to return to their original pre-activation state,
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+ or perhaps this process takes substantially longer than 14 days.
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This is a challenge for the convergence hypothesis because the ideal comparison
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This is a challenge for the convergence hypothesis because the ideal comparison
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to prove that naïve cells are converging to a resting memory state would
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to prove that naïve cells are converging to a resting memory state would
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be to compare the final naïve time point to the Day 0 memory samples, but
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be to compare the final naïve time point to the Day 0 memory samples, but
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@@ -10086,9 +10120,33 @@ negative control
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not
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not
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\emph default
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\emph default
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to be involved in T-cell activation or memory formation.
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to be involved in T-cell activation or memory formation.
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- Of course, CD4 T-cells are not the only adaptive immune cells with memory.
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- A similar study could be designed for CD8 T-cells, B-cells, and even specific
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- subsets of CD4 T-cells.
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+ Of course, CD4
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+\begin_inset Formula $^{+}$
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+\end_inset
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+
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+ T-cells are not the only adaptive immune cells with memory.
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+ A similar study could be designed for CD8
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+\begin_inset Formula $^{+}$
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+\end_inset
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+
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+ T-cells, B-cells, and even specific subsets of CD4
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+\begin_inset Formula $^{+}$
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+\end_inset
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+
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+ T-cells, such as ???.
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+\end_layout
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+
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+\begin_layout Standard
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+\begin_inset Flex TODO Note (inline)
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+status open
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+
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+\begin_layout Plain Layout
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+Suggest some T-cell subsets
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+\end_layout
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+
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+\end_inset
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+
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+
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\end_layout
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\end_layout
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\begin_layout Subsection
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\begin_layout Subsection
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