lecture 4-5 Flashcards
(51 cards)
Overview of T cells development in the thymus and activation by foreign antigens
stages involve notch signalling
- t cell precursor rearranges its t cell receptor genes in the thymus
- immature t c3lls that recognise self mhc receive signals for survival. those that interact strongly with self antigen are removed from the repertoire
- mature t cells encounter foreign antigens in the peripheral lymphoid organs and are activated
- activated t cells proliferate and eliminate infection
what are the two lineages of T cells (thymocytes) produced in the thymus
CD4+ and CD8+
T-cell precursors proliferate extensively in the thymus.
Only a few percent of the precursors survive, most cells die there and are phagocytosed by macrophages in the thymic cortex
what is the thymus’ distinct cellular architecture
the structure is made up of lobules that have distinct areas outer cortical region and inner medullary region and different cells operate in different parts of the thymus.
In the outer cortical region, we’ve got immature thymocytes, cortical epithelial cells.
The medullary region has the vasculature which allows thymocyte entry, medullary epithelial cells dendritic cells and macrophages (responsible for getting rid of those thymocytes that perhaps recognize self-AG or self-MHC too strongly) and of course mature but naïve CD8+ or CD4+ T cells
describe what happens in the cortex and medulla
CORTEX
Immature thymocytes closely associate with branched cortical epithelia cells.
Macrophages get rid of apoptotic thymocytes
MEDULLA
Mature thymocytes associate with local dendritic cells – undergoing positive and negative selection
= Thymic education – mature CD8+ or CD4+.
what happens to thymocytes in the thymus
In the thymus, thymocytes undergo rearrangement of the TCR and changes in expression of cell surface molecules
Different stages of thymocyte differentiation are found in distinct parts of the thymus
DIAGRAM IN L4 S7
map the stages of TCR and what is being expressed on the cell surface to the stages of development
map the TCRαβ rearrangement in T cell development!
L4 S8-9
role of positive selection
Positive selection ensures that all TCR bearing cells can interact with self MHC I (CD8+) or MHCII (CD4+)
Selection takes place on thymic cortical epithelial cells
MUTATIONS L4 S12
negative selection
Negative selection takes place in the thymic cortex and medulla.
- Driven by APC’s.
- T cells with TCRs which react strongly with ubiquitous self antigens are deleted in the thymus- preventing autoimmunity
- T cells with TCRs which interact too strongly with self MHC are deleted- preventing inappropriate activation
The major T cell effector subclasses and their functions in cell mediated and humoral adaptive responses
CD8 cytotixic T cells CD4 Th1 cells CD4 Th2 cells CD4 Th17 cells Tfh cells CD4 regulatory T cells (many typs)
naive T cells recirculate through secondary lymphoid organs
Naïve T cells encounter antigen during their recirculation through secondary lymphoid organs
T-cells will be effectively sampling the AG on offer.
If they recognise it they stay, proliferate and differentiate.
If not they carry on their way.
How do T cells get into lymph node?
ROLLING - selections like L-selectin
ACTIVATION - chemokines like CCL21
ADHESION - integrins like LFA-1
DIAPEDESIS - chemokines like CCL21 and CXL12
Entrance from the blood to the lymph nodes occurs through the high endothelial veinules.
It is regulated by adhesion molecules, chemokines and chemokine receptors
binding to selectins to vascular addressins
DIAGRAM IN L4 S20
L- selectin recognises carbohydrate motifs and is expressed on all T cells.
Addressins on epithelial surfaces bind L-selectin and bind T cells weakly to the endothelial surface
binding of integrins to adhesion molecules
DIAGRAM IN L4 S21
Integrins bind to adhesion molecules that are important immunoglobulin superfamily members.
These stabilise binding to APCs, HEV or endothelia
how do Lymphocytes enter the lymph nodes
Lymphocytes enter the lymph nodes by crossing the walls of the high endothelial veinules
DIAGRAM IN L4 S22
role of dendritic cells
Dendritic cells process antigen to present to T cells from a wide variety of pathogens
routes of antigen processsing and presentation by dendritic cells
DIAGRAMS L4 S23
Cell adhesion molecules are essential in the interactions between APCs and naïve lymphocytes
L-selectin is an adhesion molecule it binds to carbohydrates, here is the naïve T cell and here is the L-selectin molecule and it binds to these addressin molecules CD34 and GlyCAM-1 bound to the endothelial cell and just slows down the movement enough to stop the cell from rolling past and to start to be adhered to the wall. Slightly different addressins involved in mucosal endothelium but they do the same thing, they bind to the L-selectins and slow down the naïve T cell so that they can enter into the lymph node.
how do transient adhesive interactions between T cells and APCs stabilised
Transient adhesive interactions between T cells and APCs are stabilised by specific antigen recognition
DIAGRAM L4 S25
Naïve T cells need 3 signals to become activated
Signal 1- a specific interaction between the TCR and MHC + antigenic peptide
Signal 2- a co-stimulatory interaction which provides a survival and proliferation signal
Signal 3- a differentiation signal provided by a secreted cytokine
costimulatory signal provided by CD28:B7 binding
The costimulatory signal provided by CD28:B7 binding stimulates the production of a high affinity IL2 receptor on activated T-cells
DIAGRAM L4 S27
Variation in signal 3
Variation in signal 3 results in naïve CD4+ T cells acquiring different effector function
DIAGRAMS IN L4 S28
Different subsets of T cells roles
also role of adhesion molecules?
Different subsets of T cells are specialised to provide help for different classes of pathogens
TH1 cells TH2 cells TH17 cells TFH cells Treg cells CD8 cyt T cells CD4 TH1 cells CD4 TH2 cells CD4 TH17 cells
also remember that adhesion molecules are essential not just for the crossing of the T cells into the lymph nodes but also important in the interaction of APCs and this just shows you some of the major interactions that take place between the adhesion molecules found on the T cell and in the APC.
Partial signalling results in functional inactivation or anergy
co-stimulatory signal alone
antigen specific signal alone
DIAGRAM IN L4 S31
Most CD8+ T cell require T cell help
Interaction between a CD4+ T cell and an APC activates the T cell to produce CD40 Ligand and IL-2.
CD40L binds to CD40 on the APC providing an additional signal so that the APC increases the level of B7 and produces 4-IBBL.
4-IBBL bindings to 4-IBB on the CD8+ T cell and B7 binding to CD28 provide co-stimulatory signals to the T cell and the further production of IL-2.
IL-2 acts as a growth factor to promote CD8+ T cell differentiation.
effector t cells produced
Once an effector T cell is produced it is able to carry out its function in the absence of further co-stimulation
stimulation fo naive t cell
proloferating t cells
active effector t cells kill virus infected target cells
