(09) T Cell Effector Mechanism Flashcards
In what 2 ways do a fully differentiated effector T cell differ from that of a naive T cell?
- Effector T cells do not require co stimulation (no B7)
- Express many adhesion molecules that direct them to the correct tissue
What are the differences in the adhesion molecule expression profile of an activated T cell and an Naive T cell?
Activated T Cell:
- increases: LFA-1, VLA-4, CD2, CD44 and CD45RO
- decreases: L-selectin (CD8 only) and CD45RA
Why do activated CD4 T cells not lose their L-selectin as they mature?
L-selectin is needed to enter 2˚ lymphoid tissue. CD4 effector cells MUST enter 2˚ tissue to serve as the secondary activator of antigen-specific B cells
Why can’t CD8 T cells express L-selectin on their surface?
They would enter the 2˚ Lymph tissue and destroy all of the APCs
What does L-selectin bind?
Glycam-1 and CD34
What does VLA-4 do?
Binds to VCAM-1 found on activated endothelial cells so facilitate diapedesis
what is CD45RA?
- Marker found on naive T cells
What is CD45RO?
- Marker found on activated and memory T cells
What are the 3 main types of effector T cells?
- CD8 effector (killers)
- CD4 helper TH1
- CD4 helper TH2
What are the main effector molecules used by CD8 T cells?
- Fas Ligand
- IFN-gamma
- Perforin
- Granzymes
- Granulysin
(other cytokines - see drawing)
What is the primary effector role of BOTH types of effector helper T cells (CD4)?
- Supply the secondary activation stimuli needed to activate an antigen-specific B cell and drive their differentiation
What additional function do TH1 helper cells have?
They activate macrophages to make them more bactericidal and phagocytic
T or F: for Treg cells to perform their effector function they simply must be present in the blood
FALSE, Tregs must be present and attached to the same AP cell to prevent self-reactive T cells from functioning
Which regulators are secreted by Tregs to suppress self-reactive Tcells?
TGF-ß and IL-10
What do TH17 cells do?
**NOTE these are both indirect actions that are actually carried out by endothelial cells
Induced production of chemtractants for Neutrophils (IL-17)
Induce antimicrobial peptide formation (IL-22)
What 2 things must happen for a naive T cell to become activated?
- Recognition of cognate determinant on MHC by TCR
2. CD28 (T cell) binding to B7 on APC
What molecule is produced after the 2 activation conditions are satisfied for Naive T cells?
IL-2, the autocrine growth factor
**This leads to proliferation and differentiation
What happens to T cells after IL-2 has finished promoting proliferation and differentiation?
They move out of the secondary lymph tissue and into inflamed tissue.
- They now act as effector cells
What 3 molecules are secreted by CD8 effector cells to perform their effector function?
- Perforins
- Granulysin
- Granzymes
how do each of the following help CD8 cells perform their effector function?
- Perforins
- Granulysin
- Granzymes
Perforin - puts holes in the effector cell membrane (similar to MAC)
Granulysin - puts holes in membrane of host (and may have antimicrobial properties)
Granzymes - INITIATE APOPTOTIC PATHWAY if they get into host cytoplasm
**Note: the 1st two perform their function so that granzymes can enter an perform its function
What size holes do perforins put in the membrane?
- why does this conflict with info. about how granzymes enter the cell?
- how can we reconcile this?
- Perforin (and granulysin) create 16nm holes (NOT EVEN CLOSE TO BIG ENOUGH FOR GRANZYME)
- We can reconcile this because affected cells endocytose areas affected by pore formation. When they do granzymes enter too.
What enzyme is activated by granzymes causing apoptotic death?
caspases
Besides perforins, granzymes, and granulysins what do CD8 effectors have that helps them perform their effector function and what do these molecules do?
INF-gamma
- Drives TH0 differentiation toward TH1 which aids in elimination intracellular infection
Fas-ligand
- binds to Fas and kills host cells
What do granzymes bind to on the outer cell surface?
Cation-independent mannose 6-P receptors (CI-MPR)
What end product of the Fas cascade ultimately leads to cell death?
DNA fragments produced by CAD
Give an overview of the steps in the Fas cascade.
- Fas ligand (T cell) binds THREE Fas domain (host)
- Caspase 8 binds Fas and activates caspase 3 (via cleavage)
- Caspase 3 cleaves ICAD away from CAD
- CAD is released and starts chopping up DNA
What does ICAD stand for?
Inhibitor of CAD
T or F: CD8 cells apoptose along with the cells that they kill
NO, they simply release granules with killer contents in them
- They can continue to kill throughout their entire lifespan
How do CD8 cells prevent their granule contents from expelling everywhere causing innocent cell death?
- Polarized granulation - this means the granules go to where the MHC is bound to release their contents (this happens quickly)
What are some common intracellular bacteria?
- *Mycobacterium Tuberculosis
- Listeria monocytogenes
- Salmonella typhi
- Francisella tularensis
- Burkholeria pseudomallei
- Yersinia pestis
What type of T cell responds to a macrophage that is infected with an intracellular bacterium (like TB)?
TH1 (CD4 helper cells)
How does Macrophage activation occur via TH1?
TH1 recognizes its cognate ligand on the macrophage
- CD40 Ligand on T cell binds CD40 on macrophage
- INF-gamma from T cell binds to INF-gamma receptors on macrophage
What is the result of macrophage activation?
- Macrophage becomes better at presenting antigens (MHC I and II upregulated) and becomes more bactericidal
What specifically are the molecules upregulated by Macrophage activation?
Better APC:
- B7
- MHC class I
- MHC class II
More bactericidal:
- More NO
- MORE O2-
More inflammation:
- TNF-alpha
- THF-alpha receptor
Are the general effects of these (3 of 6) cytokines secreted from activated TH1 cells?
- INF-gamma and CD40 ligand
- Fas ligand or LT
- IL-2
INF-gamma and CD40 ligand
- activates macrophages to destroy engulfed bacteria
Fas Ligand or LT
- Kills chronically infected macrophages, releasing bacteria to be destroyed by healthy macrophages
IL-2
- Induces T cell proliferation, increasing the number of effectors
Are the general effects of these (3 of 6) cytokines secreted from activated TH1 cells?
- IL-3 and GM-CSF
- TNF-alpha and LT
- CXCL2
IL-3 and GM-CSF
- Induce macrophage differentiation in bone marrow
TNF-alpha and LT
- Activates endothelium to induce macrophage adhesion and exit form the blood vessel at the site of infection
CXCL2
- Causes macrophages to accumulate at the site of infection
What is the most important function of CD4 effector T cells?
Supplying secondary activation signals to naive B cells
What two signals are needed for B cells to become activate?
- Must be bound to cognate antigen
2. CD40-ligand (T cell) binding to CD40 on the B cell
What brings effector CD4 (TH1 or TH2) T cells into close enough proximity to allow CD40 binding?
MHC present it cognate peptide that is present AFTER the B cell (antibody) receptor brings in the molecule for endocytosis
**NOTE: because they are CD4 T cells and b/c of the method its most likely to present the antigen on MHC class II
T or F: TH1 AND TH2 cells can activate B cells
True
What is the the difference in TH1 and TH2 binding to a B cell?
TH1:
- typically fights intracellular infection so it promotes the B cell to produce IgG1 and IgG3 (strong OPSONIZERS)
TH2:
- typically fights extracellular infection so produces weakly opsonizing antibodies (IgG2, IgG4, IgA, and IgE)
What is Histoplasma capsulatum?
A fungus that lives intracellularly (inside macrophages)
***Why does granuloma formation occur with infections of Mycobacterium TB and Histoplasma capsulatum?
Even activated macrophages can’t kills these infections so Macrophages fuse and get surrounded by TH1 CD4 effector T cell
**this forms a wall preventing DISSEMINATION
Why are people with immune deficiency of T cells at increased risk for systemic infection by TB?
Granulomas don’t form because THEY REQUIRE T CELLS
- Infection can disseminate and cause systemic disease
If a Treg is bound to a cell, what can you almost guarantee about the cell?
Its a SELF cell, because Tregs are pick specifically because they do recognize self
What requirements must be met before a Treg can become activated?
- It recognizes self antigen (on MHC II)
2. CTLA-4 (Treg) binds to B7 on APC
What is released after Treg binds to MHC II (self) and CTLA-4:B7?
- why these?
IL-10 and TGF-beta are released, these down regulate any T cells nearby and decrease inflammation
What happens if you suffer from a Treg deficiency?
Autoimmune disease
