Lec 14: T cell DADM Flashcards
Do all naive T cells recognize self MHC-peptide complexes?
yes, they weakly recognize self-MHC
preferentially bind foriegn antigen but need to bind self MHC for survailence (whcih is part of the +ve selection process)
breif overview of the process of early thymocyte development
very early thymocyte development occurs in the bone marrow
then cells migrate to the thymus for further development
development of thymocytes in the thymus
talk about the different stages
positive/ negative selection stages to become single positive cells (these still have CD3)
then a final screening to remove autoreactive cells
they are then released into the peripheral bloodstream`
blerb about recombination of TCR gene segments to produce ab or gd T cells
occurs during the dn stage
TcRb rearrangements are one of the first to take place, and most likely to be productive
because of this, TcRab outsome are more likely thatn TcRgd (except in fetal development)
b-selection in DN thymocyte development
DN thymocytes undergo b-selection resulting in proliferation and differentiation
- > allelic exclusion ensures only one b-chain is rearranged. This is because we only want to express one beta chain
- > if rearrangement fails, can try again with the second
a successfully produced b chain is paried with the pre-Ta chain
- > a 33kDa protein surrogate for real TcRa chain
- > allows for formation of a pre-TcR complex (with CD3 proteins) and numerous signaling events
DP stage of thymocyte development
after b-selection has occured, thymocytes are at the DP stage
- > Functional TcRa chain replaces surrogate pre-TcRa
- > the cell still expresses both CD4 and CD8
- > Positive and negative selection occurs, yielding mature SP T cell
The affinity model of thymocyte selection
based on the strength of interaction between the TcR and self-MHC complexes
the stronger it binds, = negative selection
90% of cells fail to recognise self-MHC peptide complexes = death by neglect
In the stochastic overlap, selection towards Treg, represses responses towards self MHC antigen.
-> slightly less = naive T cell
Positive selection
intermediate affinity for MHC-peptide complex
thymocyte survival
resultrs in MHC restriction
COmmitment to either the CD4+ or CD8+ T cell lineage
most cells (90-95%) fail positive selection and do not receive need survival signals
negative selection
also known as clonal deletion
linits recognition of self
results in self-tolerance
skew cells to alternative factes, such ad Treg cells differentiaiton
less than 5% of thymocytes undergo clonal deletion
MTECS and negaive selection
MTECs have a uniqe TF AIRE which allows them to express TRA’s. These cells like to share antigen with DCs to aid in negative selection
allows new T cells to be safely screened in the thymus
Positive and negative selection ocurs in discrete thymic microenvironments
cortex and the medulla of the thymus provide microenvironments that coordinate a spatial and temporal segregation of thymocyte selection
Positive selection of ‘mainstream’ as T cells is sontingent on permissive interactions with a single APC type -> namely the cortical thymic epithelial cells (cTECs)
why are cTECs special
they have different proteasomes
different proteasomes = different peptides
cTECs have a proteasome that allows them to have the largest range of peptides
purpose of positive selection
makes sure that T cells bind a broad range of MHC-peptide complexes
Purpose of negative seleciton
negative selection (central tolerance) ensures self-tolerance
clonal deletion remains the best proven and most common method of tolerance induction in the thymus
clonal arrest
autoreactive T cells are prevented from maturing further
clonal anergy
autoreactive T cells are inactivated
clonal editing
second/thrid chance at rearranging a non-self-reactive TcRa gene
purpose fo the medulla and self tolerance
the medulla serves a crucial function for self tolerance induction
-> moreover disruption fo the 3D srchitecture of the medulla results in spont manifestations of autoimmunity
the medulla is a mosaic of self antigen
Tonic TcR signalling
T cells are selected based on the strength of interaction between the TcR and self-MHC complexes
resting T cells display a range of affinity for self, which generates a scale fo tonic signalling in vivo. -> engagesd but recognition is not sufficient to drove a response.
sub-threshhold tonic signals do not activate T cells, rather promote lymphocyte survial and modulated their function.
Relevance of CD5 for T Cells
more CD5 = stronger binding to self MHC peptide complexes
CD5 expression levels on SP thymocytes are thought to reflect the signalling intensity of the positively selecting TcR-MHC interaction
-> tuned CD5 levels persist on mature peripheral T cells as a footprint of thymic selection
what does re-exposure of mature T cells to their positively selecting pepetide(s) for
is necessary for homeostasis through continual tonic TcT stimulation
CD5 in models of infection
CD5 hi Tcells for response to pathogens, CD5 high can outcompete
-> they react more strongly and are selected for because of the better immune response
biased T cell selection towards strongly self-reactive clones endows them with a homeostatic advantage and a head start in anti-pathogen responses
how many signals are responsable for T cell activation
3 signal hypothesis
Signal 1 of T cell activaiton
antigen-specific TCR engagement
Signal 2 of T cell activation
contact with costimulatory ligands
Signal 3 of T cell activation
cytokines direct T cell differentiation into effector cell types
- IL 2 has autocrine actions for T cells
- BInding IL 2 induces T cell proliferation during activaiton stages
- Polarizing cytokines promote T cell differentiation into specific subsets
Immunmological synapses
cSMAC
pSMAC
interactions can be as long as 3-4 hours
cSMAC
central supramoleculer activating complex
TCR/MHC peptide complexes and co-recpetores centralize
pSMAC
peripheral supramolecular activaitng complex
adhesion molecules. bound ligands peripherally localize
positive costimulatory receptors
facilitate actiaviton
CD28 and ICOS
CD28
44kDA glycoprotien expressed on the majority of T cells
Markedly enhances TCR induced proliferation and survival
binds to CD80 and CD86 expressed by APCs, involved in initial activation
ICOS
inducible costimulator, binds ICOS-ligand on activated APCs
expressed on memory and effector T cells
= actrivation
Negative costimulatory receptors
help turn activaiton off
CTLA-4 (CD152)
PD-1 (CD279)
CTLA-4 (CD152)
induced within 24 hours after activaiton, peaks 2-3 days post-stimulation
binds to CD80/86 with higher affinity than CD28
puts the brakes on
PD-1 (CD279)
PD-1 may help to mediate T cell tolerance in non-lymphoid tissues
inhibition
T cell anergy
clonal anergy results if a costimulatory signal is absent
helps provide tolerance, especially in the periphery
if only MHC-peptide signal is recieved, cell is rendered non-responsive
anergic cells cannnot respond to subsequent challenge, even in the presence of costimulation
BLockade of CD28-CD80/86 interaction can render naive T cells anergic
this essentially resets the threshold for activation so high that it will never activate even with costimulation
T cell differentiation
depends on interactions between APC and T cell
PRR signalling influences APC adn T cell interactions
Polarizing cytokines from APC or surroundng milieu influence T cell differentiation
T cells aquire an effector state
-> not fixed, T cells can be repolarized under the right conditions
give an example of T cell differentiation
on the final
Naive CD4+ T cell -> Il-12 and IFNg triggers TF T-bet to induce differentation into a Th1 cell
Secretion of IFNg and TNF then can lead to machophage activation and inflammation
T-bet
is a TF that promotes differentiation to a Th1 cell
Importance of T cell differentiation
folicular Th cells
follicular helper T cells are CD4+ T cells that bprovide help to B cells
-> CD40L-CD40 interactions and the release of cytokines
CD4+ T cells can also helop mediate the initial generation of antiviral CD8+ T cells effector responses
T helper cells contribute to the character of inflammatory responses in the tissue
example with Th1 cells
inflammatory = Th1 -> IFNg and Th17
CD4 indcution to cytotoxic cells
-> kill infelced APC’s
T cell DC interactions and activation is a two way street
T helper cells can directly activate DCs
memory T cells can activate DCs and bypass the need for PRR activated costimulatory signals
Enhances innate immunity
-> is substantialy quicker and more effective that PRR-triggered responses alone
thus, memory cells can make the innate immune responses more robust
type of memory T cells
not all effector T cells have equal potential to form memory T cells
terminal T effector cells (short-lived)
Long-0lived Tem memory cells
Longest-lived CCR7+ Tcm central memory cells
Trm resident memory cell
Longest-lived CCR7+ Tcm central memory cells
reside in and traffic between secondary lymphoid organs
Trm resident memory cell
reside in epithelial barrier tissues, the first site of antigen during an infection
How are T cells selected in the thymus
write out a long answer response
what is central tolerance and how is it achieved
Central tolerance, also known as negative selection, is the process of eliminating any developing T or B lymphocytes that are reactive to self. Through elimination of autoreactive lymphocytes, tolerance ensures that the immune system does not attack self peptides
mTECs and cTECs
What is tonic TcR signalling, and what is the purpose of it
???
What signals are required to activate a naive T cell? what happens if a key signal is absent?
???
Make a table discussing the phenotype and function of
Th1 cells Th2 cells Th17 cells Treg cells Tfh cells
