Immunology - T-cells & development Flashcards
Compare & contrast the mechanisms leading to activation of CD4+ & CD8+ T cells & the role of MHC in this process.
Naive lymphocytes leave thymus, use blood stream to patrol/look for antigens by visiting secondary lymphoid tissue (spleen, MALT, thyroid, etc.) and using cell-surface molecules (eg L-selectin) that act as homing receptors that enable them to “remember” locations of High Endothelial Venules (“tube stops” for lymphocytes to exit the blood circulation). This is the same for all naive T-cells after they leave the thymus, before they differentiate further and then proliferate.
**1. SIGNAL 1: **Immunological synapse
MHC:peptide complex binds with naive T-cell’s TCR
2. SIGNAL 2: Co-stimulation by dendritic cells’ CD80/86 molecule + T-cells CD28 molecule (accelerator)
After immunological synapse, if there’s a real “danger” detected, then the DC/APCs become **stimulatedvia pattern-recognition receptors and/or inflammatory cytokinesto express CO- STIMULATORY MOLECULES CD80/CD86that “mesh” like transmission/clutch with theT-cells’ CD28** molecule
- IMMUNE RESPONSE GENES ACTIVATED (IL-2) - PROLIFERATION of T-cells
- ** DIFFERENTIATION INTO CD4+ or CD8+ EFFECTOR T CELLS**
What are CD8+ T cells?
Cytotoxic killer T cells.
They leave the lymphoid tissue for the bloodstream, and instead of looking for HEVs using their homing receptors, they alter their homing receptors and instead go to targeted tissue.
After differentiation into CD8+ T cells, they no longer need the co- stimulation of CD80/86 & CD28 to become activated.
CD8+ recognise antigens in cell cytoplasm (viral usually) presented by infected cells via the MHC I pathway & cause apoptosis by use of:
i/ perforin/granzyme/caspase cascade;
ii/ Fas/Fas-ligand interaction
iii/ cytotoxic cytokines tumour necrotic factors (TNF-alpha & TNF-beta)
What happens after naive T-cells differentiate into CD4+ helper cells?
These T-cells can differentiate into Th-1 and Th-2.
Th-1 (talk to macrophages): These T-cells secrete IFN-gamma to stimulate/anger macrophages, which go into endosomal-lysosomal overdrive aka Respiratory Burst, producing oxygen free radicals, NO and antimicrobial proteases to KILL vesicular pathogens (ie., these are pathogens engulfed by macrophages into endosomes & lysosomes.
Th-2 (talk to B cells): These T-cells secrete B-cell growth factor IL-4 that causes naive B cells to mature into plasma cells in the extracellular fluid and secreting antibodies in the blood. The Th-2 cytokines also tell the B cell which types of immunoglobin (receptors/antibodies) to make depending on the type of bacterial infection.
What role do Tregs play in the immune response?
Toward the end of an infection, T cells will start down-regulating CD28 (accelerator) to prevent SIGNAL 2 from causing the T-cell treat the interaction with the APCs’ CD80/86 signals as “danger” signs.
Instead, it starts expressing CTLA-4 along with CD-28, to act as a “brake” on the “clutch” system.
Natural Tregs are usually CD4+ T-cells that are produced after an animal is born. They produce IL-10, and immunosuppressive cytokine that damps other CD4+ cells. *** CHECK THIS
Induced Tregs (Tr1 cells) also differentiate from naive CD4+ T cells, toward the end of an immune response along with memory T cells. They also express IL-10.
What are Th-3 cells?
TH-3 (Helper T cells Type 3) are produced in MALT in response to antigen stimulation in mucosal surfaces (gut, respiratory, etc.) and produce cytokine Tranforming Growth Factor-beta (TGF-beta) to stimulate IgA production.
What are memory T cells and what is their role in the imne response?
Memory T cells differentiate toward the end of infection immune response and act as the reserve troops. They’re long-lived and re-enter immune surveillance along with naive T cells.
Naive T-lymphocytes leaving the spleen and bloodstream have “homing” receptors to exit points into lymphoid tissue such as the MALT (mucosal-associated lymphoid tissue eg., Peyer’s Patches) and lymph node. ‘
What are these exit points called?
High Endothelial Venules
HEVs are specialized post-capillary venous swellings characterized by plump endothelial cells as opposed to the usual thinner endothelial cells found in regular venules. They are “high” because of their thickness.
HEVs enable lymphocytes circulating in the blood to directly enter a lymph node (by crossing through the HEV).
HEVs enable naïve lymphocytes to move in and out of the lymph nodes from the circulatory system. HEV cells express addressins, which are specific adhesion molecules that attach to the L- selectins on lymphocytes and anchor them to the HEV wall in preparation for crossing the endothelium.
Why are HEVs necessary for the activation of naive T-cells (cells that have no yet committed to becoming CD4+ helpers or CD8+ killers)?
In order for an adaptive immune response to occur, T cells need to be activated.
T cells become activated by recognising foreign antigens bound to antigen presenting cells (APC), in particular, dendritic cells.
In order for naïve T cells to bind to their specific antigen, they need to experience physical contact with those cells.
Since antigen levels are usually low, contact in blood circulation would be unlikely. Therefore, T cells need a region where they can go to sample foreign antigens that have entered the body.
When an APC, such as a dendritic cell, binds a foreign antigen it becomes activated and moves into the lymph nodes (sites for antigen sampling by T cells) via afferent lymphatic vessels.
Naïve T cells in the circulation regularly move through the lymph nodes via HEV in order to scan the APC for foreign antigens. When they encounter such an antigen, the cell becomes activated, resulting in the immune system mounting a response against the causative agent of the infection.
CD8+ T cells are only able to recognise:
a) Intracellular antigen peptides presented by MHC Class I molecules expressed by all nucleated cells
b) Extracellular antigen peptides presented by MHC Class II molecules presented by APCs
c) Whole extracellular pathogens whose epitopes bind to the variable segments of soluble receptor
d) Extracellular antigen peptides that knocks off the CLIP peptide left behind in the peptide groove by the degraded chaperone protein
e) Extracellular peptides from antigens in the infected cell’s cytoplasm transported to the ER by TAP transporters
a & e
CD8+ T cells recognise intracellular antigens (mostly viral) presented by MHC Class I molecules by all nucleated cells.
The antigen peptides, usually found in the cell cytoplasm from viral synthesis, are transported into the ER by TAP proteins, where they are LOADED onto the MHC I’s peptide groove. The peptide-MHC complex is then transported via Golgi up the cell’s surface, where the CD8+ cell recogises it.
What is the purpose of the CLIP protein that occupies the peptide groove in MHC II molecules?
It’s a placeholder to block MHC II from accidently binding to intracellular peptides (eg., viral) transported into the ER from the cytoplasm by TAP proteins while the MHC II molecule is still inside the APC (dendritic cell, macrophages, B cells).
The CLIP peptide is the remnant of the chaperone protein (invariant chain) that helps form the MHC II molecule. The chaperone degrades after the MHC leaves the Golgi in a vesicle, leaving only the CLIP.
The CLIP is knocked off once endocytosed extracellular peptide that has been lysed by the APC merges with the MHC-CLIP vesicle.
The MHC II: antigen peptide complex are then transported to the surface.
Which APCs present extracellular antigen peptides via MHC Class II to naive T-cells in the lymph nodes to stimulate proflieration & differentiation?
a) B-cells
b) Macrophages
c) Neutrophils
d) Dendritic cells
d
Dendritic cells
Which APCs present extracellular antigen peptides to mature CD4+ T helper cells?
a) B cells
b) Macrophages
c) Neutrophils
d) Dendritic cells
a & b
B cells and macrophages
Where do dendritic cells present antigen they have encountered to naive T cells?
Paracortex of lymph nodes
Via which vessel do dendritic cells travel from the blood stream to reach lymph nodes for antigen presentation?
Afferent lymph
What is the importance of CD3 in the activation of T cells?
CD3 is a T-cell co-receptor that activates the T-cell once the main TCR is bound to an antigen peptide presented by an MHC molecule.
