Cytotoxic Cell-mediated Immune Response Flashcards
What identifiers are expressed on resting mature naive T cells?
CD4 or CD8 CD28 HLA class I TCR complex with CD3 LFA-1 and VLA-4 adhesion molecules Chemokine receptors
Mature naive T cells express CD28, what is this a receptor for?
CD80 (B7-1) and CD86 (B7-2)
What is the only constitutively expressed B7 receptor on naive T cells?
CD28
What is the result if a TCR binds an APC without CD28:B7 interaction?
Anergy
Where are naive T cell responses initiated?
Peripheral lymphoid organs, like LNs
Innate immune responses aid in initiation of T cell activation through generation of inflammation. What cell type ALONE is capable of activating naive T cells?
Dendritic cells
If only DCs can activate naive T cells, what are the roles of B cells and macrophages as APCs in the adaptive immune response?
B cells and macrophages activate memory T cells
What cells are responsible for activating the B cells and macrophages that can then activate CTLs?
CD4 T cells
Naive T cell activation begins when they enter the LN via ___________ in the cortex
High endothelial venules
Once the naive T cell has crossed the high endothelial venule in the cortex of the LN, what happens if it does not encounter a specific Ag?
It will leave the LN through efferent lymphatics
Once in the LN, naive T cells monitor antigen presentation by what 2 cell types?
Macrophages
Dendritic cells
T cells that encounter specific antigen proliferate and differentiate to effector cells, resulting in cytokine production.
Which type of T cells increases to the greater degree upon Ag recognition?
CD8+ T cells increase more
[CD4 increase 100-1000x, while CD8 increase 100,000x]
Within ____ days of antigen appearing in a LN, it has been bound by its naive antigen specific T cell
____ days after the arrival of Ag, activated effector cells emigrate from the LN into periphery
2
5
What is the primary function of CD3 in the TCR-APC immunological synapse?
Signal transduction by TCR complex
What is the primary function of zeta chains in the TCR-APC immunological synapse?
Signal transduction by TCR complex
What is the primary function of CD4 in the TCR-APC immunological synapse, and what is its ligand?
Signal transduction (coreceptor, stabilization)
Ligand: Class II HLA (on APC)
What is the primary function of CD8 in the TCR-APC immunological synapse, and what is its ligand?
Signal transduction (coreceptor, stabilizing)
Ligand: Class I HLA (on APCs and CTL targeting cells)
What is the primary function of CD28 in the TCR-APC immunological synapse, and what is its ligand?
Signal transduction (costimulation)
Ligand: B7-1/B7-2 (on APC)
What is the primary function of CTLA-4 in the TCR-APC immunological synapse, and what is its ligand?
Signal attenuation
Ligand: B7-1/B7-2 (on APCs)
What is the primary function of LFA-1 in the TCR-APC immunological synapse, and what is its ligand?
Adhesion
Ligand: ICAM-1 (on APCs and endothelium)
What is the primary function of VLA-4 in the TCR-APC immunological synapse, and what is its ligand?
Adhesion
Ligand: VCAM-1 (on endothelium)
What term is used interchangeably for B7-1/B7-2?
CD80
What is the general T cell activation pathway?
Formation of synapse
Activation of 2 tyrosine kinases:
1. Fyn –> phosphorylation of ITAMs of CD3 and zeta chains
- Lyk (src family) –> phosphorylates and activates tyrosine kinase ZAP-70 associated with zeta chain
PLC activation leads to two potential transcription factors, NFAT and NFkB. How does PLC activation lead to NFAT?
Increased cytosolic Ca2+ –> calcineurin –> NFAT
PLC activation leads to two potential transcription factors, NFAT and NFkB. How does PLC activation lead to NFkB?
DAG –> PKC –> NFkB
How does T cell activation lead to AP-1 transcription?
Via Ras-MAPK pathway, production of RasGTP and ERK, JNK
In addition to LFA-1 and VLA-4, what else is present on the T cell mediating adhesion in the immunological synapse?
CD2 (binds LFA-3 ligand on APC)
When a T cell first recognizes antigen presented by an APC, there is weak adhesion and NO T cell response. What changes occur in order to generate a stronger interaction?
APC releases chemokines that activate integrins on the T cell surface –> the integrins will cluster together and increase their affinity (via conformational change), leading to strong adhesion and a T cell response
What process is often necessary for full CD8 T cell activation?
Cross-presentation
both CD4 and CD8 bind to DC presenting antigen. CD4 will release cytokines to the CD8 cell to help activate it
Activation of T cells triggers a cascade of protein production.
Once change involves increase in ______ expression on T cells, which interacts with a receptor on APCs to strengthen adhesion, hence prolonging T cell-APC contact
CD40L (binds CD40 on APCs)
Activation of T cells triggers a cascade of protein production.
What transcription factors are likely to be produced in response to T cell activation?
c-Fos
c-Myc
Activation of T cells triggers a cascade of protein production.
What membrane effector molecules are likely to be upregulated during T cell activation?
CD40 ligand
Fas ligand
Activation of T cells triggers a cascade of protein production.
What cytokines are likely to be secreted during the T cell activation process?
IL-2
IFN-y
IL-4
Activation of T cells triggers a cascade of protein production.
What cytokine receptors are likely to be upregulated during the process of T cell activation?
IL-2R
There are several cytokines produced by T cells once they are activated. What is the principle action and cellular source of IL-2?
Survival, proliferation, differentiation of effector and regulatory T cells
Source: CD4 and CD8 T cells
There are several cytokines produced by T cells once they are activated. What is the principle action and cellular source of IL-4?
B cell switching to IgE
Source: CD4 T cells, mast cells
There are several cytokines produced by T cells once they are activated. What is the principle action and cellular source of IL-5?
Activation of eosinophils
Source: CD4 T cells, mast cells
There are several cytokines produced by T cells once they are activated. What is the principle action and cellular source of IFN-y?
Activation of macrophages
Source: CD4 and CD8 T cells, NK cells
There are several cytokines produced by T cells once they are activated. What is the principle action and cellular source of TGF-beta and IL-10?
Inhibition of T cell activation; differentiation of Treg cells
Source: CD4 regulatory T cells; many other cell types
What type of signal is IL-2?
Autocrine
Describe the expression and affinity of IL-2R on T cells.
IL-2R is constitutively expressed as a low affinity receptor
Binding of IL-2 leads to expression of IL-2Ralpha chain, which forms HIGH affinity complex
Binding of IL-2 to high affinity IL-2R promotes T cell proliferation and differentiation
Which cytokines, present at the site of infection, cause the naive CD4 cell to switch to Th1?
IFN-y
IL-12
Which cytokines, present at the site of infection, cause the naive CD4 cell to switch to Th2?
IL-4
Which cytokines, present at the site of infection, cause the naive CD4 cell to switch to Th17?
TGF-beta
IL-6
IL-23
Th1 cells are characterized by IFN-y secretion. What 3 functions does this cytokine perform when released from Th1?
Activates macrophages
Activates B cells to stimulate complement binding
Stimulates class II HLA and CD80 on B cells
Other than IFN-y, what cytokine does Th1 produce?
TNF-alpha
What cytokines are released from Th2 cells?
IL-4
IL-13
IL-5
Th17 cells release several cytokines, but which one is considered characteristic of Th17 cells?
IL-17
What are the 2 primary functions of IL-17 released from Th17 cells?
Barrier function
Neutrophil activation
How do bacterial superantigens differ from typical antigens in their activation of T cells?
Bacterial superantigens can activate T cells in the absence of co-receptors and co-stimulation
Where does a bacterial superantigen bind in the TCR-APC complex?
Alpha chain of MHC class II
V-beta region of TCR
Where does a viral superantigen bind in the TCR-APC complex?
Beta chain of MHC class II
V-beta region of TCR
What are some of the consequences of superantigen activation?
Fever, rash
Edema, hypotension, shock –> multiple organ failure
What 2 cytokines are primarily responsible for multiple organ failure during superantigen activation? How do they do this?
TNF-alpha and IL-1
These contribute to an increase in vascular permeability that leads to leakage of fluid from the intravascular space into the perivasculature
What is the major difference between effector T cells and resting naive T cells?
An effector T cell is able to respond to specific antigen without the need for costimulation via CD80-CD28 interaction
During T cell activation, where do antigen recognition, proliferation, and differentiation take place?
In the lymph nodes
How do activated effector cells travel to the site of infection?
In the blood
After activation by APCs in the ________ area, CD4+ Th cells change their chemokine receptor expression and migrate to the edge of the _________ zone.
Activated Th cells secrete low levels of cytokines and increase expression of co-stimulatory molecules; eventually they will start expressing _______
Medullary; follicular
CTLA-4
How do the Th cell chemokine receptors change in order to cause migration of activated T cells to the edge of the follicle?
Decreased expression of CCR7
Increased expression of CXCR5
[note that B cells in the B cell zone will upregulate CCR7 to move toward T cell zone]
What general effect do interferons have on cytotoxic T lymphocytes ability to kill?
They increase HLA expression for T cell recognition
True or false: the host cell must be killed in order to eliminate an intracellular pathogen via CTLs
True
Stored lytic granules that contain cytotoxins are released directly onto the surface of the infected target cell (perforin + granzymes)
What are the 2 mechanisms of CTL killing?
Granular proteins (perforin and granzymes)
FasL and Fas (CD95)
What do the granular enzymes released by CTLs do to target cells?
Perforin forms pore necessary for delivery of granzymes
Granzymes activate caspases in cytosol –> apoptosis
What is the Fas/FasL mechanism for CTL killing?
Activated CTLs express FasL which binds death receptor Fas on target cells. This interaction results in activation of caspases and apoptosis
How does cooperation exist between CD4 and CD8 T cells?
CD4 cells release IFN-y, causing killing of microbes in phagolysosome of phagocyte
CD8 then comes in and kills the entire infected cell
What cytokines enhance NK cell killing?
IFN-alpha
IFN-beta
IL-12
What inhibits NK cell killing?
MHC class I binding inhibitory receptor
What cell markers are found on NK cells?
CD16
CD56
What intracellular signaling event prevents activation of NK cell killing when the inhibitory receptor is engaged by MHC I?
Removal of phosphates from the PTK just inside the membrane
ADCC involves what 5 cell types?
NK cells
Macrophages
Neutrophils
Eosinophils
ADCC involves target recognition through which Ab?
IgG
What are the killing components of ADCC?
Lytic enzymes
TNF
Perforin/granzymes
With chronic infection, the viral load remains somewhat constant and CTLA-4 is continuously upregulated. This eventually leads to Th cell ____________
Exhaustion
What two cellular components are upregulated in chronic infection induced CD8 T cell exhaustion?
CTLA-4 (binds B7 on target)
PD-1 (binds PD-1L on target)
What happens to most of the effector cells generated in response to a specfic antigen once that infection has been cleared?
They are short-lived. Only some become memory T cells.
What do memory CD4 and CD8 T cells require to regain their effector functions?
They require reactivation, as well as IL-7 and IL-15 for survival
What allows our bodies to react much more quickly to secondary infection?
Memory T cells do not need coactivators to respond, so they are able to quickly kill the pathogen on secondary infection
Is CTLA-4 expression on Treg cells inducible or constitutive?
Constitutive
Treg cells constitutively express CD4, CD25, and CTLA-4
What is the unique TF associated with Treg cells?
FOXp3
Tregs express CTLA-4, what does this bind to and what does that cause?
CTLA-4 binds CD28 and shuts down IL-2 production
Which binds more avidly to CD28: CD80 or CTLA-4?
CTLA-4 binds more avidly to CD28
PD-1 is a regulatory receptor that is inducible on what cell types?
T cells
B cells
myeloid cells
This causes negative regulation of T cells
What receptor is inducible on T cells and operates as a costimulator as well as in generation of follicular helper T cells?
ICOS
Binds ICOS-L on DCs, macrophages, B cells, and others
What cytokine-related evasion mechanism is used by EBV to avoid our immune response?
EBV makes an analog of IL-10 leading to inhibition of macrophage and DC activation
What type of bacteria evade our immune system by inhibiting phagolysosome fusion?
Mycobacteria - they are able to survive within the phagosome
What type of pathogen evades our immune system by inhibiting antigen presentation?
HSV (inhibits TAP)
CMV (removal of MHC I from ER, inhibits proteosome)
EBV (inhibits proteosome)
What type of pathogen evades our immune system by blocking cytokine activation of effector cells?
Pox viruses - they produce soluble cytokine receptors that take up any cytokines around so that they cannot bind to receptors on effector cells
