Cytokines, Interleukins, Cell Targets, and Receptors Flashcards
Name the two differences between naïve and armed effector T-Cells.
- They do not require costimulation to perform their functions. They only need the recognition of their cognate peptide presented by an MHC molecule.
- They express an array of surface adhesion molecules that direct them to the appropriate tissues and inflammatory sites.
L-Selectin (or CD62L)
- Expressed on the surface of NAIVE CD4 and CD8 T-Cells
- Bind to adhesion molecules (CD34 and GlyCAM-1) found on the surface of endothelial cells that line HEV on secondary lymphoid tissue.
What is required for cells to enter secondary lymphoid tissue via HEV?
L-selectin
Is L-Selectin found on the surface of of effector CD8 T-cells?
NO! They have no positive role in these tissues. In fact, it would be negative for them to be there because they would kill APCs presenting their cognate peptide on MHC molecules.
Do CD4 effector cells need to have L-Selectin on their surface?
NO. This allows them to cycle through various secondary lymphoid tissues to serve as secomdary activaotrs of AG-specific B cells .
What is upregulated on the surface of effector T cells?
VLA-4
What does VLA-4 do?
It binds VCAM-1 that is expressed on activated endothelial cells, facilitating the movement of the effector cell across the vascular endothelium into an inflammatory site.
What marker is found on naïve T cells?
CD45RA
What marker is found on activated and memory T-cells?
CD45RO
What are the three main types of effector Tcells?
- CD8 effector cells (CTLs or killer T-cells)
- TH1 type effector CD4 T cells
- TH2 type effector CD4T cells
What is the primary function of CD8 effector T cells?
kill infected cells resulting in premature termination of the replicative cycle of the pathogen
What are the effector molecules produced by CTLs?
- Fas Ligand, perforin, granzymes, granulysin
2. also some cytokines important for development of the immune response.
What is the primary role of effector CD4 Tcells?
supply the critical secondary activation stimuli needed to activate an Ag-specific B-cell and drive their differentiation (done by both Th1 and Th2)
What is another function of Th1 cells?
activate macrophages, making them more phagocytic and more bacteriocidal
CD-40 Ligand
an effector molecule of CD4 cells along with their cytokines
Function of Treg cells?
prevent activation of self reactive Tcells
Function of Th17 cells?
induce production of neutrophil chemotractants and antimicrobial peptides
What are the cytokines secreted by CD8 effector cells?
IFN-gamma and LT
What are the cytotoxins secreted by CD8 Tcells?
perforin, granzyme, granulolysin
What two signals of activation does a naïve T cell require?
- recognition of a cognate antigenic determinant via the TCR
- costimulation in the form of B7 molecules on the APC binding to CD28 on the T cell
What does IL-2 stimulate?
T cell proliferation
Describe T cell proliferation
The daughter T cell fully differentiate into their effector cells and move into inflamed tissue and sample peptide:MHC complexes. If they recognize their cognate peptide bound to MHC they will perform their effector functions
What is the action of perforin?
inserts into the host cell membrane as a multimer complex, forming pores in the cytoplasmic membrane of the cell
What is the action of granulysin?
forms pores in the cytoplasmic membranes of cells; also appears to have antimicrobial properties
What is the action of granzymes?
They are serine proteases that initiate the apoptotic pathway if they gain access to the host cell cytoplasm.
What is the purpose of killing the infected host cell?
This halts the replicative cycle of the intracellular pathogen and causes the release of pathogens that have accumulated in the cell making them more susceptible to other immune responses (i.e. complement, antibodies/phagocytosis)
Are the holes created by perforin and granulolysin large enough for granzyme to fit through?
NO
Repairative Endocytosis
This is how we currently think granzyme gets into the cell. When the cytoplasmic membrane of the host cell becomes damaged, the cell repairs the segment by emdocytosing the damaged segment. Granzymes bind to a receptor on the host cell membrane and whent he damaged emebrane is endocytosed, the granzymes are carried into the cytoplasm of the host cell. Once inside, they initiate the caspase cascade, resulting in apoptotic death.
IFN-Gamma
a cytokine that drives differentiation of Th0 to Th1
**This is critical because Th1 cells are critical for the clearance of intracellular pathogens
Fas Ligand
A protein that can initiate programmed cell death by binding to Fas on the surface of host cells
How many copies of Fas does a single Fas ligand bind to?
3
Describe what happens when Fas Ligand binds three copies of Fas.
Binding of Fas Ligand brings together the intracellular domains of the 3 copies of Fas and causes them to undergo a conformational change that makes them a template for binding by adaptor proteins that have “death” domains. These adaptor proteins recruit and activate caspase 8, which cleaves caspase 3 and activates it. Caspase 3 then cleavs ICAD, which becomes active. ICAD then enters the host nucleus and destroys the host cell DNA by cutting it into pieces.
Where is Fas ligand located?
It is confined to the inside of the cytotoxic granules of CTLs and becomes exposed when the CTL degranulates.
How many signals do effector T-cells need to activate?
ONE! Tey only need to recognize their cognate peptide Ag bound to an appropriate MHC molecule.
How many infected host cells can one CTL kill?
Many. CTLs can regenerate their granule contents and continue to kill cells bearing their cognate peptide Ag for the duration of their life.
Briefly describe peptide sampling
Integrin LFA-1 on the CTL binds to ICAM on the host cell. This brings the two cells close enough for the CTL to sample peptide:MHC complexes via their TCR. If it doesn’t recognize it, it releases from the cell. It continues this process until it encounters its cognate peptide.
Describe how CTLs release their granules.
They do so in a polarized fashion so they kill their target cell without affecting neighbor cells.
What cells are responsible for the activation of macrophages?
Th1
List some intracellular pathogens
viruses, Listeria monocytogenes, Mycobacterium tuberculosis, Salmonella typhi, Yersinia pestis
What two signals are required for macrophage activation? ( this is done when Th1 effector Tcell recognizes its cognate AG on MHCII)
- CD-40 Ligand on Tcell binds CD40 on macrophage
2. the Tcell produces IFN-gamma that binds to IFN-gamma receptors on the macrophage
Describe the purpose of fulliy activating the macrophage.
It will be more phagocytic, a better APC (via upregulaiton of MHCi, MHCII, and B7), and more bacteriocidal (via upregulaiton of oxygen intrmediates and NO production).
Name the products secreted by Th1 cells
Fas Ligand, lymphotoxin, IL-2, IL-3, GM-CSF, TNF-alpha, CXCL2 (MIP)
Why do Th1 cells express Fas Ligand and Lymphotoxin?
This enables them to killworn out macrophages that are chronically infected. This results in the release of the pathogen so that fresh macrophages can take them up and destroy them.
Why do Th1 cells produce IL-2?
It serves as an autocrine growth factor for Tcells, promotes Tcell activation, and therefor increase the number of effector Tcells.
Why do Th1 cells produce IL-3 and GM-CSF?
They induce macrophage differentiation in the bone marrow.
Why do Th1 cells produce TNF-alpha and lymphotoxin?
They activate vascular endothelium resulting in easier movement of macrophages to inflammatory sites.
Why do Th1 cells produce CXCL2?
This acts as a macrophage chemotactic factor that promotes accumulation of macrophages.
What two signals do B-cells require for activation?
- recognitnion of their cognate antigenic determinant through their BCR
- activation stimuli from Tcells (i.e. CD40 binding, production of cytokines from the helper B cell
What happens when a B cell recognizes its cognate determinant?
It endocytosis it and displays it using MHCII. When wither Th1 or Th2 recognize this, they supply the CD40 ligand and cytokine signals to activate the Bcell.
What cytokines are produces by Th1 cells?
IFN-gamma GM-CSF TNF-apha LT IL-3
What type of class switching do the cytokines produced by Th1 cells induce?
They switch to Ab types that are strong opsonizers i.e. IgG1 and IgG3 for the best clearance of intracellular infections.
What cytokines are produced by Th2 cells?
IL-4 IL-5I L-10 IL-13 TGF-beta
What type of class switching do the cytokines produced by Th2 cells induce?
They switch to Ab types that are weakly opsonizing i.e. IgG2, IgG4, IgA, IgE for the best clearance of extracellular infections.
Where are Th1 cells usually found in a granuloma?
around the periphery
What is the primary function of Treg cells?
They prevent activation of self reactive naïve Tcells.
Describe the TCR repertoire of Tregs
IT is very limited with specificities that are mostly limited to self determinants.
What happens when a Treg recognizes its cognate determinant and also receives its additional signal (CTLA-4 binding to B7 on APC)?
It will produce and secret TGF-beta and IL-10. These two have anti-inflammatory properties and act on any T cell that is also sampling peptides on that APC, making it less likely that that T cell will become activated.
What do Th17 cells produce?
IL-17 and IL-22. These stimulate epithelial cells to produce neutrophil chemotractants and antimicrobial properties.
IL-2
- Produced by Th1 cells, CTLs, naïve Tcells following activation
- Promotes proliferation and growth of Tcells
IFN-Gamma
- Prodiced by Th1 cells and CTLs
- Required for macrophage activation, NK cell activation
- Involved in the interferon response that makes host cells less susceptible to viral infection
Lymphotoxin (LT of TNF-beta)
- Produced by Th1 cells and CTLs
- Provides activation stimuli for macrophages, encouraging NO production
IL-4
- Produced by Th2 cells
- Supports growth and survival of Th2 cells
- Promomtes class switching to IgE
IL-5
- Prodiced by Th2 cells
- Primary driving signal for class switching of B cells to IgA
- Promotes growth and differentiation of Eosinophils
IL-10
- Produced by Th2 cells and Tregs
- Has anti inflammatory properties that result in the inhibiton of cytokine release by macrophages
IL-3
- Produced by both Th1 and Th2 and CTLs
- Serves as a growth factor for hematopoietic progenitor cells in the bone marrow
TNF-alpha
- Produced by Th1 and Th2
- Activation signal for macrophages
- Activator of vascular endothelium
GMCSF
- Produced by Th1 and Th2 and CTLs
- Serves as a growth factor for hematopoietic progenitor cells in the bone marrow resulting in increased production of macrophages and granulocytes
TGF-beta
- anti inflammatory cytokine released by Tregs
- prevents the activation of self reactive T cells
IL-17
- Produces by Th17
- Serves as a signal for induction of neutrophil chemokines by endothelial cells
IL-22
- Produced by Tregs
- Serves as a signal for induction of antimicrobial peptide production by endothelial cells
Through what pathway does cytokine binding work?
Jak-STAT
