(08) T Cell Activation and Differentiation Flashcards
Where does T Cell activation occur?
- why?
- ONLY in 2˚ lymphoid tissues
- Only place where there is sufficient contact between APCs and T cells
- this is the only place that the concentration of T cells is high enough to find the right match
What 2 signals must be sent before a T cell will activate?
- T-cell binds to an MHC II and recognizes its peptide determinant
- B7 on the APC binds to CD28 on T cell
Why are professional APCs the only cells that can activate T cells?
They are the only cells with B7 and both signals are needed for activation
How do T cells get from the bloodsteam into 2˚ lymph tissue?
- cells?
- Stepwise.
- Naive T Cell L-Selectin (selectin) binds CD34 and GlyCAM-1 (Addressins) of High Endothelial Venule
- cell slows down and is rolling - Chemokines on HVE cell recognized by Chemokines like LFA-1 on Naive T-cell
- signal is sent to T-cell nucleus - T-cell is activated and can now bind tightly to ICAM-1 (Chemokine) via LFA-1 (Chemokine)
- interaction between HEV and T-cell tightened - Diapedesis occurs
What are the 4 classes of cell-surface adhesion molecules?
- Selectins (bind Addressins)
- Mucin-like Vascular Addressins (target of selectins)
- Integrins (bind ISM)
- Immunoglobulin Superfamily Members (target of integrins)
What types of problems might result from not having enough or cell-surface adhesion molecules or molecules that are dysfunctional on immune cells.
Immune deficiency, adherence is a key part of initiating immune response
- antigen encountered?
- antigen not encountered?
s
What would result from a lack of ICAM-1 from APCs or LFA-1 from T-cells?
T Cells would not be able to get close enough to sample the environment of the APC and immune deficiency would result
- *What allows EFFECTOR T cells to bind activated endothelial cells?
- when can this happen?
VFA-4 and VCAM-1, this happens after INFLAMMATION has occurred
Differentiate E and L selectins.
Location:
- E selectin - vascular endothelial cells
- L selectin - High vascular endothelial cells
Cells with associated Addressins:
- E selectin - neutrophils, macrophages, T cells, eosinophils, NK cells, TUMORS
- L selectin - Naive T cells
What cell types can express B7?
- what does B7 do and when?
- what does it pair with?
- ALL professional APCs (macrophages, dendritic cells, and B cells)
- B7 on APCs pairs with CD28 on T cells
- it ONLY is expressed when the APC is in 2˚ LYMPHOID tissue
Although all professional APCs participate to some degree in all infections, what APCs are typically most active in:
- viral infections
- bacterial infections
Viral Infections - Dentritic Cells
Bacterial Infections - Macrophages
BOTH - B cells
How do B cells present antigens from something like a bacterium?
- Ig binds to cognate determinant
- bacterium in endocytosed
- peptides are displayed via MHC class II
Dendritic cell
- location
- antigen uptake method
- MHC expression
location:
T cell zone
antigen uptake method:
+++ Macropinocytosis
Phagocytosis by tissue dentritic cell in viral infection
MHC expression:
- Low on tissue dendritic cells
- High on dendritic cells in lymph tissue
Dendritic Cell
- Co-stimulator Delivery
- Antigen Presented
- Location
Co-stimulator Delivery:
++++ Constitutive by mature, nonphagocytic lymphoid dendritic cells
Antigen Presented:
- Peptides
- Viral Antigens
- allergens
Location:
Ubiquitous Throughout the body
Macrophage
- location
- antigen uptake method
- MHC expression
location:
Everywhere in lymph node
antigen uptake method:
+++ Phagocytosis
MHC expression:
Inducible by bacteria and cytokines (- to +++)
Macrophage
- Co-stimulator Delivery
- Antigen Presented
- Location
Co-stimulator Delivery:
Inducible (- to +++)
Antigen Presented:
Particulate antigens
Intracellular and Extracellular Pathogens
Location:
Lymphoid tissue
Connective Tissue
Body Cavities
B Cell
- location
- antigen uptake method
- MHC expression
location:
in lymph follicle (germinal center)
antigen uptake method:
Antigen-specific Receptor (Ig) ++++
MHC expression:
Constitutive and increases on activation +++ to ++++
B Cell
- Co-stimulator Delivery
- Antigen Presented
- Location
Co-stimulator Delivery:
Inducible (- to +++)
Antigen Presented:
Soluble Antigens
Toxins
Viruses
Location:
Lymphoid Tissue
Peripheral Blood
Suppose a viral infection gets into the skin epithelium what APC would be MOST likely to respond?
- explain stepwise how this response gets to APCs.
- Langerhans (dendritic) Cells would be most likely to respond because they are ubiquitous
1. Langerhans cells without B7 would be efficient at antigen uptake
2. It would migrate through lymphatics to a node
3. Inside node it would differentiate into an professional APC and B7 would be expressed to activate CD28 on a T-cell
T or F: levels of MHC class I and II as well as B7 is dramatically up regulated in ALL APCs when PRRs engage a PAMP
True
How might Dendritic cell sensitivity to viral infection be explained by adhesion?
- Dendritic cells express DC-CK (dentritic cell cytokine) which allows them to interact more closely with Naive T cells
- Ability to get closer means more sampling, and more reaction. T cells are known to be particularly sensitive to the VIRAL response
What happens when a B-cell endocytoses some pathogenic material?
- stepwise.
- how does presence of PAMPs change this?
- Material will be degraded and attached to MHC class II molecules on surface
- Naive or Effector T cell encounters the peptide-MHC II
- CD4+ effector causes B cell activation
- CD8+ effector cell kills B cell
IF PAMPs also encountered:
- B7 will be expressed allowing for even closer association with T cells
Compare inactivated macrophage to an inactivated dendritic cell.
- what causes activation
- what changes?
- Niether immature macrophages or dendritic cells can present to Naive T cells
- PAMP encounter causes activation
- B7, MHC class I and class II are drastically upregulated making it a good APC
What binds ICAMs on APC surface?
- what would happen if ICAM or its partner were messed up?
ICAM (intercellular adhesion moleule) binds to LFA-1 (lymphocyte function associated antigen)
- LFA-1 to ICAM binds is vital because it brings APCs and Tcells into close enough proximity that CD4 and CD8 and recognize MHC II and MHC I
What are the relative affinities of:
- LFA-1 to ICAM-1 (before and after conformational change on binding)
- CD4 to MHC class II
- TCR for cognate peptide
Least: LFA-1 to ICAM-1 (before conformation change) LFA-1 to ICAM-1 (after conformation change) CD4 to MHC class II (equal to LFA-1 to ICAM
MOST:
- TCR for Cognate Peptide
how do the recognition abilities of Effector T cells differ from those of naive T cells?
Naive T cells only recognize peptide that’s bound to MHC molecules
T or F: a single TCR can bind its cognate peptide and the Naive T cell will be activated
FALSE, there is a threshold that must be met before anything changes
What 2 steps are required for a T Cell to become activated?
- Cognate Peptide recognition via APC
- Costimulation - CD28 (T cell) binds to B7 on APC
- ACTIVATION can now occur
What does it mean for a T cell to become activated?
1st - Clonal Expansion
2nd - IL-2 and IL-2 Receptor are produced
What is IL-2?
- what does it do?
- Interleukin-2 (IL-2) is an AUTOCRINE growth factor because the cell also makes the receptor for IL-2
- IL-2 drives the T cell proliferation
How does an activated T cell sensitize itself to IL-2?
- IL-2 and IL-2 receptor are produced on activation
- when IL-2 levels get high enough a 3 subunit (alpha subunit) is produced for the IL-2 receptor that makes the receptor more efficient at detection
What if you lose ability to synthesize the following for IL-2:
- alpha (high affinity subunit)
- Gamma
- Beta
- loss of any of these leads to SCID because T Cells will not proliferate as they should
What is the back up mechanism for T Cells that make up all the way through thymic development?
Peripheral Tolerance
- Naive T cells require B7 receptors to activate and become effector cells
Problem for Self Recognizing TCRs:
- there will be no B7 present when these cells get activated (presumably this is quite frequently) because not APC have recognized PAMPs
- cells bound by TCR and not by B7 become anergenic and die soon after
Note B7 binding without MHC binding does nothing
Note B7 binding without MHC binding does nothing
T or F: PRRs are only located in the cell membrane
False, there are also cytoplasmic PRRs for things like telling the cell to make B7
Why do are autoimmune diseases believed to manifest after bacterial invasion?
Mechanism of Peripheral Tolerance is bypassed and B7 becomes present to interact with self-recognizing T cells:
How:
- Self-antigens are present (as is normal for a macrophage)
- Bacteria in environment is recognized via PRR and gets broken down and its antigens are presented on MHC I
- B7 gets put on cell surface
- self-recogizing T cell binds Macrophage and has B7 to activate it and allow it to clonally expand
Which has higher affinity for APCs?
- CD4 or CD8
- why?
CD4 because CD8 needs to have a lower affinity so it doesn’t kill everything
Which of the APCs expresses the highest level of B7 on their cell surface?
- consequence?
Dendritic Cells can present antigens to CD8+ without assistance in order to activate them
Can macrophages activate CD8+ on their own?
- if not what else is required?
No, they don’t express enough B7 to do it on their own.
- CD4+ T Cells that bind with higher affinity can bind MHC class II and activate Macrophages to produce more B7
B-cells lack sufficient numbers of B7 receptors to activate CD8+ on their own. What allows them to ever bind to CD8+?
- CD4+ helper T cells binds B cell (or Macrophage) and secretes IL-2.
- IL-2 from helper cell can be taken up by CD8+.
- CD8+ cell can be activated in spite of the APC not expressing much B7
What are the major differences between an effector T cell and a naive T cell?
- B7 costimulation is not required for effector cells to perform their function
- Effector T cell have adhesion molecules that target them to specific tissues in the body
Cytotoxic T cells
- most active against what type of infection?
- why this type of infection?
- Cytotoxins?
- Cytokines?
Active against:
- Viral Infections
Why viral activity? - CD8 is expressed to binds to MHC class I, which provides intracellular sampling
Cytotoxins:
- Perforins
- granulzymes
- granulysin
Cytokines:
- IFN-gamma
- LT
Of the two types of helper T cells, which is most effective against viral infections?
- why?
TH1
-Promote and immune response that is effective against intracellular infections (cell-mediated)
**Note: TH2 promotes ANTIBODY responses that are more effective against extracellular infections
What is the effect of TH1 and TH2 on macrophages?
TH1
- up regulates macrophage activation
TH2
- down regulates macrophage activation
TH1 Cells
- most active against what type of infection?
- why this type of infection?
- Cytotoxins?
- Cytokines?
Most Affective:
- Viral Infection
Why?
- promote immune response specific for intracellular pathogens
Cytotoxins:
- NONE - helpers not killers
Cytokines:
- IFN-gamma ***
- IL-2 ***
- GM-CSF
- TNF-alpha
- LT
- IL-3
TH2 Cells
- most active against what type of infection?
- why this type of infection?
- Cytotoxins?
- Cytokines?
Most Active:
- Bacterial
Why?
- enhances ANTIBODY production for Extracellular infections
Cytotoxins:
- NONE - helpers not killers
Cytokines:
- IL-4 *** (MOST IMP.)
- IL-5 ***
- IL-6 ***
- IL-10 ***
- IL-13
- TGF-ß
What cell type do TH1 and TH2 initially start as?
TH0, undifferentiated cells
How to do TH0 cells initially arise?
Naive CD4 T cells are activated and begin proliferating, this creates TH0 cells
What cytokines lead to differentiation of TH0 cells into TH1 and TH2 cells?
TH1:
- IL-12
- INF-gamma
TH2:
- IL-4
- IL-5
- IL-6
- IL-10
What two main factors drive TH0 differentiation?
- Cytokines Present in environment
2. Concentration of MHC class II with bound peptide
How do differences in concentration of antigen direct TH0 differentiation into either TH1 or TH2?
TH1
- Promoted with HIGH concentrations of MHC bound antigen
- concentration is high because virus or bacteria is replicating inside the cell
TH2
- Promoted by LOWER concentrations of MHC bound antigen
- Lower concentration favors TH2 formation because it indicates that infection is outside the cell
Tregs
- what are they derived from?
- When?
- What are the driving factors?
Derived from:
- TH0 cells in the thymus
When:
- During NEGATIVE SELECTION in Thymic development (early in life)
Driving Factors:
- TSLP is produced by HASSAL’s corpuscles
- TSLP acts on medullary dendritic cells to upregulating B7 and cytokines (TGF-ß)
Treg
- what drives expression of its cytokines
- cytokines secreted
- Most potent?
Cytokine expression driven by:
- FoxP3
Cytokines Secreted:
- TGF-ß (MOST POTENT)
- IL-10
What does TGF-ß do?
Suppresses Activation and Differentiation of T-cells
Once distributed in the body, what is the function of Tregs?
- Detect self antigens (happens b/c they are derived from self-reactive T-cells)
- Once self antigens have been detected TGF-ß and IL-10 are produced
What is the flow of cytokines that induce production of transcription factors that cause differentiation into:
- Treg
- TH1
- TH2
Treg:
- cytokine TGF-ß induces transcription factor FoxP3 causing diff. to Treg
TH1:
- cytokines IL-12 and INF-gamma induction transcription factor T-bet
TH2:
- Cytokine IL-4 (as well as IL-5, 6, and 10) induces transcription factor GATA-3
What functions are carried out by type 17 helper T cells?
- cytokines?
produces cytokines
IL-17 - neutrophil chemotractant causing PRO-INFLAMMATORY response
IL-22 - induces ANTIMICROBIAL peptide formation by epithelial cells
