T cell plasticity Flashcards
why do T cell have heterogeneity?
-Inflammation and healing during the course of immune response
- Cytokines change during the course of infection/disease
- Many diseases require multiple types of immune responses
why is it important to understand T cell plasticity?
- T cell phenotypes determine disease progression and patient outcomes
- Immune therapies try to target T cell subsets
- Limitation to date is understanding the extent of T cell heterogeneity and polarisation
what are polyfunctional T cells?
Populations that don’t exist in theory but in reality do
when do heterogenous T cells exist?
In health and in disease
how do we need to study heterogeonous T cells?
uncouple phenotype and function
what is heterogeneity?
T cells can do lots of different things
what is plasticity?
T cells can change what they do
how can T cells change?
at a signle cell, or population level
what does the reversible maturation of T cells mean?
Reversible maturation process allows cells to undergo alternate fates depending on environment
what signals T cells to differentiate?
Early cytokine signals
what enforces T cell differentiation?
Master regulator transcription factors
how can T cells be plastic?
Other signals can reprogramme the differentiation
- Some cells are more or less likely to switch between Th cell forms
what regulates different T cells subsets?
- Cytokine mediated inhibition
- Transcriptional inhibition of T cell subsets (master regulators)
- Epigenetic control of T cell subsets (Histone modification, methylation)
- TCR signalling
What controls T cell subsetss?
Cytokine combinations can drive hybrid T cells
- some cytokines can inhibit other cytokines
Transcriptional control of T cell subsets
Epigenetic control of T cell subsets
T cell receptor signalling strength
how do cytokines control T cell subsets?
- some cytokines can inhibit other cytokines
Cytokine combinations can drive hybrid T cells
what is transcriptional Inhibition of T cell subsets?
-During T cell differentiation towards one lineage, the other lineage fates are usually suppressed
- mutual exclusivity among master transcription factors
- Cross regulation through repression of transcription factors
what are the master regulators of T cell subsets?
Tbet- Th1
GATA3- Th2
RORyc- Th17
FOXP3- Treg
what are the different types of transcriptional regulation?
- Pioneer
- Antagonism
- Synergy
- Competition
- Redistribution
- modulation
what is pioneer transcriptional regulation?
initial polarising signal (STATs that coordinate a cytokine (+) signal to get transcription of more cytokines
what is antangonism transcriptional regulation?
Transcription factors competing for binding sites (-)
-Cytokines don’t exist in isolation
- Multiple STATs can be activated and compete with each other for binding sites
what is synergy transcriptional regulation?
Transcription factors finding friends to help them bind (+)
- Might need another protein (co-factor) to help the transcription factor bind
what is transcriptional regulation through competition?
Transcription factors fighting over their friends (-)
- Common molecules required for binding
(RUNX1 is a co-factor that both RORy and FOXp3 need to bind- who wins when competing for the co-factor)
what is transcriptional regulation through redistribution?
Transcription factors move to new places (+,-)
- sometimes two different transcription factors are expressed and they can bind in different places
what is transcriptional regulation through modulation?
transcription factors change activity of other molecule (+)
- one transcription factors can change the binding of another transcription factor
how does epigenetics control T cell subsets?
-Epigenetics control activation and repression of genes
- Differentiated T cells (Th1, Th2, Th17) divide and daughter cells keep the same differentation program by
i) self reinforcing transcription factor networks
ii) epigenetic mechanisms = stanble and heritable programme BUT with ability to changes
what are the two major mechanisms for epigenetic change?
- methylation of DNA (usually repressive= gene silencing)
- chromatin/histone remodelling (activation or repression)
what can we do to know that epigenetics is involved?
- Inhibit histone modification and see what happens
- Inhibit DNA methylation and see what happens
how is T cell receptor strength used to regulate T cell differentation?
- TCR affinity generates different signalling strength pathways in a cell
- This can lead to activation of different transcription factors and therefore different cytokine genes
how can cytokine genes effect T cells?
- Turning the recpetiveness of a cell to different cytokines
- Inducing the expression of specific cytokine receptors
- Impinging directing on the activation of specific STATs
how are T cell subsets controlled?
- Cytokines
- Transcription factors
- Epigenetic mechanisms
