Lecture 7- T cell activation Flashcards
where are different T cells found?
Conventional CD4 and CD8 T cells migrate through the blood and secondary lymphoid organs
CD4 T cells are the most numerous T cells within lymph nodes
Unconventional T cells mainly found in pathogen-exposed tissues
Natural Killer T cells: liver, lung, bone marrow
Mucosal Associated Invariant T cells: mainly in gut
γδ T cells in skin and mucosal tissues
how are Unconventional T cells are often activated in infected tissues?
MAIT T cells = amplify immune response
γδ T cell = amplify or regulate immune response
NK T cell = kill infected cells
what is the overview of CD4 and CD8T cell response
- Pathogens infect tissues
- Activated DCs move to lymphoid organs carrying the pathogen
- DCs activate antigen specific T cells
- T cell proliferate
- T cells migrate out of the lymph node
- T cells migrate to infected tissues to clear infection
what does T cell activation lead to?
Proliferation:
more antigen specific cells to control or clear the pathogen
Differentiation:
T cells alter their functions to tailor their response to the pathogen
how are T cells activated by mature DCs
- PRR triggering enhances phagocytosis
- Pathogens are digested inside endosomes
- MHC molecules inside endosomes meet pathogen- containing endosomes
- MHC molecules containing peptides from pathogen are presented on the cell surface
- PRR triggering causes the DC to migrate from the tissue to the draining lymph node
- PRR triggering also causes the DC to express high levels of costimulatory molecules and make inflammatory cytokines
what are Major Histocompatibility Complex I?
-MHCI is expressed by all nucleated cells
-Recognised by CD8 T cells
-In most cells, the peptides presented on MHCI are from proteins produced by the cell itself (endogenous pathway)
what are Major Histocompatibility Complex II?
MHCII is (mostly) expressed by professional Antigen Presenting Cells: macrophages, DCs, B cells
Recognised by CD4 T cells
In most cases, the peptides presented on MHCII are from proteins that the cells picks up from outside itself (exogenous pathway)
what are Endogenous versus Exogenous Presentation Pathways?
Endogenous Pathway: mostly MHCI =
-Cell infected by intracellular pathogen
-Pathogen proteins broken up by proteasome
-Peptides loaded onto MHCI in Endoplasmic Reticulum
Exogenous Pathway: mostly MHCII =
-Cell takes up pathogen by phagocytosis
-Pathogen proteins broken in endosome
-Peptides loaded onto MHCII in endosome
what is negative selection?
removes T cells that recognise the body’s own proteins- MOSTLY
Single positive T cells undergo negative selection in the medulla
They interact with epithelial cells and DCs
Thymic epithelial cells express many different self peptides that are found in organs throughout the body
This is coordinated by a molecule called AIRE
Cells that recognise self-peptide MHC with high affinity can undergo cell death
what are factors of costimulation molecules?
they are diverse and numerous
what are the different ways to stop T cells responding
Ignorance = T cells cannot access antigens in immune privileged sites
Presentation of antigen by resting DC = T cells die or become non-functional (anergic) if activated by signal 1 alone
Presentation of antigens from environmental antigens leads to tolerance preventing allergy
Regulatory T cells = Thymic Tregs stop T cells from responding to self peptides preventing autoimmunity
Sometimes this leads to the induction of new regulatory T cells = Induced or iTregs recognise peptides from pathogens or innocuous proteins
They also stop T cells responding to activated DCs – help prevent autoimmunity and allergy
how Activated CD8 T cells differentiate into killer/cytotoxic T cells
When activated CD8 T cells recognise infected cells they release molecules that make holes in the infected cell: Perforin
And release granules that fuse with the infected cell releasing proteins that cause apoptosis: Granzymes
They can also kill infected cells via cell surface receptors such as Fas or release chemokines/ cytokines that call in and activate innate cells at sites of infection
CTLs can also recognise cancer antigens and kill cancerous cells
describe T cell activation in the lymph node…
Afferent lymph vessels: where cells come in from the tissue
B cell follicles: where germinal centres form during immune responses
Paracortex: naïve T cells
The majority of these are CD4 T cells
Paracortex: where DCs from the tissue meet naïve CD4 and CD8 T cells
how does DC pick up antigen and present it to CD4 and CD8 T cells in MHC II and MHC I respectively
Exogenous antigen taken up by dendritic cells is presented on MHC I and II
DC present peptide-MHC II to CD4 T cells and peptide-MHC I to CD8 T cells
There are specialised DC that are particularly good at presenting exogenous Ag on MHC I
This process is called cross-presentation
what does CD4 and CD8 T cell activation require?
3 distinct signals, at least two of which are provided by the activating dendritic cell. The second part of the cartoon illustrates that the activated T cell proliferates generating more T cells with the same TCR.
T cell differentiation requires continued activation and sustained differentiation signals
Activation leads to division of the T cell
This is T cell clonal selection and leads to lots of cells with the same T cell receptor
Most of the time conventional T cells migrate through the blood and lymphoid organs…
High Endothelial venules (HEV): T cells can move directly from the blood into the lymph node
T cells scan dendritic cells looking for their specific antigen presented on either MHC I or MHC II
These brief interactions with self-peptide MHC provide survival signals
