Cellular Immune Response II: T Lymphocytes, Antigen Presentation And NK Cells Flashcards
lymphocytes are responsible for antibody production and graft rejection
Ok
T cells are generated from precursors in the ___ ___
Bone marrow
In the bone marrow rearrangement of the genes produces what
Receptor for the antigen
Then t lymphocytes leave the bone marrow and go to lymph nodes as __, or ___
Naive immature
Properties of a naive T cell
- functional rearrangement and expression of their surface receptors for an antigen
- a reduced or absent tendency to recognize self antigens
Where do naive T cells become activated
In lymph nodes when antigens are presented to them as short peptides on MHC
The only APC capable of activating naive T cells is ___
DC
After T cell activated get functional polarization. What is functional polarization
T cell takes on a particular set of tastes that promote the adaptive immune response , effector or regulatory functions
Like organizing B cell responses
Where is the pre T cell
Bone marrow
Where is there selection of T cells with appropriately rearranged receptors for antigen
Thymus
Where are naive T cells
Lymph node
Where fo T cells encounter antigen bearing DC
Lymph node
Where do T cells carry out effector functions
Peripheral tissue
Where are memory T cells
Lymph node
CD3 complex
On T cell
Collection of molecules that transduce activation signals
5% of TCR are what
Y and delta
What are they two receptor options for tCr
Ab or gammadelta
What are the two types of T cells
CD4 and CD8
Are there more cd4 or cd8
1/3 8
2/3 4
Host helper cells have what receptor
Ab
Most cytotoxic have what receptor
Gammadelta
T cell surface markers
TCR and CD3
All T cells are thymus derived
CD4
On helper T cells 66% of all T cells
Interact with MHCII
CD8
On cytotoxic lymphocytes
33% of T cells
Interact with antigen presentation by MHC class I molecules
___ T cells are lost in HIV
Cd4
Flow cytometry
For T cells
Cell subset quantification exploit three items:
- Existence of a surface molecules
- Monoclonal antibody specific for the molecule
- Chemicals called fluorochromes that fluoresce at a particular wavelength when exposed to an excitatory light source
A suspension of cells from a patient is incubated with monoclonal antibodiesthat have been tagged with fluochrome of choice. Fluorochrome glows different colors. What do fluorescein, phycoerythrin, and allophycocyanin glow
Green orange then red respectively
The cells labeled with fluochrome are exposed to a laser, viewed and counted. What technique is this done by
Flow cytometry
Basic flow cytometry
- Cells identified by the way they scatter light in the forward direction(dependent on size) and at 90 degrees (dependent on granules in cytoplasm)
- Machine analyzes whether a particular cell has been bound by the monoclonal antibody
High light scattered at 90 degrees
Granular cell, neutrophil
Low or no light scatter at 90 degrees
Angular cell like a lymphocyte
High light scattered forward
Large cell, like a neutrophil
Low or no light scatter forward
Small cell like a lymphocyte
High fluorescence from labeled antibodies
Cell stained, like a B cell
Low or absent fluorescence emission from labeled antibodies
Cell not stained like a T cell
How can DC help prevent reactions against self
Only guides responses when danger signals are present , could give stop and go advice when initiating immune response
What if T cells generated tcr that bound with such high affinity that they do not require dc to become activated
Autoimmunity
Pre T cells
No surface markers can not be identified as T cells and they go to the thymus
What are precursor T cells called in the thymus
Thymocytes
How long does thymic education for a cell emerging into the periphery take
3 weeks
How long is a thymocytes in the thymus when not destined for selection
3.5 days
Facts about mature T cell
Tcr are rearranged and the tcr dimer expressed, along with cd3 and one accessory molecule, either cd4 and cd8
Cd4 response with MHCII
CD8 with MHCI
Describe path of pre T cell from bone marrow to thymus
Pre T cell leaves bone marrow by blood and either the thymus as a thymocyte through blood. It migrates to the cortex, expands and then follows a series of interactions quite epithelial cells in the cortex and medulla as well as with dendritic cells before leaving the thymus as a naive T cell
Thymic education
T cell acquired tools of their trade in the thymus
There is an extensive thymocyte death, only _% of precursor cells entering the thymus leave as mature cells
1
Despite the enormously broad repertoire of possible TCR configurations, in health relatively few mature peripheral T cells are able to make responses to self antigens
Yup
Three basic elements of thymocyte selection
- Discard all tcr that are incapable of interacting with self MHC molecules
- Discard al tcr with dangerously high affinity for self MHC (negative selection
- Select tcr that are between these two extremes (positive selection)
T cell negative selection
Get rid of undesirable
T cell positive selection
Keep good quality
The arriving thymocyte migrates to the ___ of the thymus and undergoes twenty fold expansion
Cortex
When the pre T cell arrives at the thymus, is there a T cell receptor, cd4 or cd8?
Nope
Double negative stage
No cd4 or cd8
For the DN thymocyte, do tcrb or tcra chains rearrange first
Tcrb
At this stage, the tcrb chain pairs with an invariant ___-
Tcr a chain that assists signalling through cd3 complex
If the thymocyte fails at the first checkpoint, it will die. What is the thymocyte at the first checkpoint
Thymocyte in thymus with tcrb and an invariant pre tcra chain with cd3
This checkpoint looks for successful productions of tcrb
If it passes the first checkpoint(good tcrb) what will the DN thymocyte express next
Both CD4 and CD8 and rearrange the tcra chain
Now there is an tcrab dimer
What is a cthymocyte called that expresses both CD4 and CD8
Double positive (DP)
What does the thymocyte look like at the second checkpoint
Has TCRab dimer, and CD4 and CD8
The DP loses one Cd4 or CD8 and becomes what
Single positive. SP4 SP8
If cells are separated from an active thymus, stained for cd4 and cd8. What will you see
Different DN, DP and SP stages
What happens when SP4 or SP8 interact with mTEC
MHC
90-95 % of thymocytes fail in a 3-4 day window (SP) and die. What is this death called
Death by neglect
Where does death by neglect happen
Thymic cortex and
What is death by neglect in the thymic cortex mediated by
Cortical thymic epithelial cells (cTEC)
SP cells migrate towards the thymic medulla fromthe cortex, where they interact with ____
Medullary TEC (mTEC)
What do mTEC do
Express proteins that would not be found anywhere other than in specialized peripheral organs (insulin, trypsin, complement——>mirrors peripheral self
Have transcription factors that allow them to express this wide variety of gene products
AIRE gene
Transcription factor from mTEC
Humans deficient in AIRE
Syndrome in which multiple manifestations of self reactive T cells
So. MTECs display peripheral self antigens to enable what
Deletion of any SP T cells processing TCRs capable of very strong binding too self
What happens to SP T cells that have strong binding to self antigens when presented by MHC
Actively deleted, negative selection , on T cells with high avidity for self antigens
A feroprotein is presented my mTEC. Where is it from
Liver
Where is serum amyloid P
Liver
Where is trypsin
Pancreas
Where is insulin
Islet of Langerhans
Where is glutamic acid decarboxymlase
Islet of langerhans
Where is somatostatin
Islet of langerhan
Where is crystalline
Eye
Where is retinal s antigen
Eye
Where is thyroglobulin
Thyroid
How long are thymocytes in the thymus being educated
3 weeks
Qualifications for thymocyte to survive
Productive rearrangement and expression of TCRabTCR capable of moderate interaction with MHC
Affinity for self antigens cant be too high
What happens after positive selection
T cell goes to periphery where as a naive T cell it resides in the lymphatic system
What do naive T cells do in the lymphatic system
Recirculate between nodes and blood
Ready for dc to represent antigens
What important marker is on CD4 T cells for B cell activation
Cd40L (CD154)
What does cd40l on T cell bind to
Cd40
What are th major functions of T cells Cd4
Activation from dc
Recruitment and activation of specialized cd8 cells in antiviral response
Signalling for B cell expansion
Secretion of cytokines for growth and differentiation of a range of cell types
Regulates immune reactions
Is CD3 required for T cell function
Yes
What are some accessory molecules-important additional signals and interactions
CD3, 4, 8
CD28
In clinical , what are monoclonal antibodies able to identify
Different T cell associated molecules and can be used to subdivide the total T cell population into T cell subsets
What is the CD3 complex analagous to
B cell receptor complex
What does CD3 do
Closely associated with TCR and functions to transduce signals that follow from interaction with peptide MHC molecules, to initiate the process of T cell activation
The antigen receptor has no signalling properties like the B cells. How does cd3 transmit signal
Cd3 complex whale immunoreceptor tyrosine based activation motifs (ITAMs) leads to activation of intracellular activation cascade, triggering tyrosine kinase activationa nd calcium signalling and ultimately leading to changes in gene expression profiles
The CD3 complex is composed of five different transmembrane protein chains denoted what
Gamma, delta, epsilon, zeta and eta
One epsilon chain associates non covalently with a delta chain and this complex lies adjacent to the a chain of the TCR
Ok
An epsilon gamma complex associated with the b chain
Yup
Nearby there is a zeta zeta homodimer (%) or a zeta eta heterodimer (%)
90 10
What are cd4 and cd8
Accessory molecules in T cell function
Describe cd4
Transmembrane glycoproteins monomer
Member of immunoglobulin supergene family
Has 4 immunoglobulin like domains
What does cd4 do
Adhesive forces between interacting cells by binding to the b2 domain of class II MHC molecules not he APC and provides an accessory activation signal through a lymphocyte specific protein tyrosine kinase called Lck
___ is the cellular receptor for HIV
CD4
Describe the cd8
Disulphide linked dimer having a single immunoglobulin like domain
A and b chains
What does cd8 do
Cell adhesion Binds to a3 domain of the class i MHC , stabilizing T cell interactions with APC or target cells while its cytoplasmic domain becomes phosphorylation
B cells see free antigens. Do T cells
No MHC restricted
What kind of peptides are presented to cd8
Internal antigens like viruses
What kind of peptides are presented to cd4
External antigens from microbes
Proliferation assay
Lymphocytes separated from whole blood (densities)
Blood layered onto a solution of fixed density then centrifuges
List order of cells after centrifuge from top to bottom (least dense to most dense)
PBMC preparation
Light cells(platelets) Moderate density cells (lymphocytes, monocytes) Dense cells (RBC, granulocytes )
Selected populations can be further purified using monoclonal antibodies coated with magnetic beads
Yup
The proliferation assay requires responding T cells and antigen presenting cells all of which are contained in the PBMC prep, to be incubated with the antigen for 3-6 days. A radioactive source of dna base thymidine is then asses and incorporated into the new dna of dividing cells
The radioactive nuclei of the cells are collected into a filter and the radioactive emission counted . This provides a measurement of the T cell proliferation response to antigen
Describe the exogenous pathway
Pinocytosis(DC), receptors for antigen (mannose receptor and DC-sign
Anter an antigen is internalized by a B cell in the exogenous pathway, where does it go
Late endosomes
What happens in late endosomes
Fuse with lysosomes
Low pH
Antigen degradation
How does an antigen get into B cell
Pinocytosis (DC cell) Antibody (B cell) Complement receptor Fc receptor Mannose receptor
APCs continually make ____ which is assembled in the ER
MHCII
Transcription and translation and processing of MHCII is ____ when AC are activated
Upregulated
*parallels DC and PRR
Newly formed MHCII travel via the __ to come in contact with late endosomes
Golgi
The antigen binding grow of MHCII is protected throughout irs journey through the cytoplasm from accepting peptide antigens by the presence of ___ ___ (_)
Invariant chain (li)
What does Ii chain do
Acts as a chaperone for MHCII
Promotes assembly of new MHCIIab heterodimers
Targets newly synthesized class II MHC into endosomal pathway PROTECTS pEpETIde binding groove
What part of the Ii chain occupies the MHC groove and prevents any other self peptide from binding
CLIP region (class II associated invariant chain peptide)
Where does peptide load MHCII
Group of vesicles in a late endosome compartment termed MIIC (MHC class II compartment)
What happens in the MIIC
Ii chain is released and a new peptide from exogenous antigens is inserted into the groove
What molecules catalyst loading of peptide into MHCII and losing Li
HLA-DM in APD
In B cell an additional HLA-DO
In the late endosome/lysosomes what is degreasing the protein
Low pH, AEP, GILT, cathespins
GILT
Gamma inducible lysosomal thiol reductase
Cleaves disulphide bonds
AEP
Asparaginyl endopeptidase
Cleaves asparagina (N) residues
Together what do GILT and AEP accomplish
Unfolding! Antigens relax after disulphide bonds are cleaved or removal of N
Cathespins
Enzymes with broad specificity that cleave at both ends of proteins
Describe endogenous pathway
Peptides from fragments of endogenously synthesized proteins
Where does antigen peptide loading take place of MHCI
In the ER, where B2 microglobulin and MHCI heavy chains assembled
The assembly of a peptide loaded MHCI molecule depends upon 3 components
Heavy chain, B2 microglobulin and calnexin
What is calnexin
Acts as the molecular chaperone for class IMHC It lives in the ER and ensured that assembled MHCI associate with peptide int he correct compartment and also stops MHCI with empty grooves from leaving the ER
Calreticulin
Chaperone molecule that ensures that the a heavy chain and B2 microglobulin are stable until antigenic peptide is loaded
How do peptides arrive in the ER int he endogenous pathway
ATP dependent TAP1 and TAP2 (transporter associated with processing..genes lie in class II MHC region) They act as funnels into the ER and can also select based on size(8-10 aa) and appropriate sequence for class I binding
Tapasin
TAP transporters are kept in close proximity to the waiting class I molecule by. Tapasin Also increases stability of intermolecular interactions
What is the peptide loading complex made of
4 calreticulin
4 tapasin
TAP1, TAP2
What does calnexin do
Chaperone for protecting empty groove
What does calreticulin fo
Chaperone for maintaining stability in absence of peptide (MHCI)
TAP1 and TAP2
Transportation into ER and editing of cytoplasmic peptides
Tapasin
Brings empty classs I molecule close to loading site
Proteosome
Generates peptides for loading
Proteosome
Large complex of proteases with multicatalytic capabilities
Big enoug to see on electron microscopy
What does proteosome look like on electron microscopy
Cylinder shape like a cotton reel
4 rings and 7 cylinders with a hollow core
What cells does proteosome process
Ones that have been tagged with ubiquitin
What would a protein by ubiquinated
Surplus of misfiled
PSMB8, PsMB9
Immunoproteosome, only found in dendritic cells (also encoded on MHCII region)
TAP and PSMB are found on MHCII region gene. What does this mean
Influence of one region of MHC on the other
How do viral proteins synthesized in the Er load mhcI
Retrograde translocation
Retrograde translocation
ER associated degradation (ERAD) stayed
Subversion of the immune system
Microorganisms evolve mechanisms to evade the immune system
Strep pneumonia and Neisseria meningitidis
Complex capsular carbohydrates that prevent access of antibodies and complement to bacterium
Kaposi Sarcoma associated herpes virus
Tumor of lymphatic vessel endothelium
Genome has several viral homologues of human immune modulator genes (il-3, 6)
RNA viruses
High mutational frequencies
Herpes simplex and its encoded ICP47
Cytotoxic protein that binds TAP1/2 diners to prevent peptide binding and entry into the ER lumen
Cross presentation
Property of DC
Once viral proteins are acquired from the external milieu and internalized into the endosomal compartments for antigen presentation, they must. Then undergo retrograde translocation into the cytoplasm
How do viral proteins undergo retrograde translocation
With a protein conducting channel, Sec61
What does retrograde translocation allow
DC to process , present and display int he lymph node the same virus peptide-MHC complex that the CD8 CTL will encounter int he respiratory tract
How do we activate T cells artificially in the lab (al T cells)
Use polyclonal activator or mitogen-PHA(cross links surface glycoproteins on T cells), or monoclonal anti-CD3 (cross links the TCR complex).
PMA with a calcium ionophore
Superantigens(endotoxin B staph)
How do we activate a specific T cell artificially
Specific antigen of peptide epitope is added to cultures
How do we detect cytokine responses of T cells
Elisa
Flow cytometry-detect inside cell
Pcr-detect cytokine specific mRNA transcripts quantified by PCR
What new method is used to quantify antigen specific T cells
Use recombinant DDNA technology to make soluble HLA molecules which are loaded with the peptide epitope of interest
The HLA molecules are assembled into complexes of four peptide HLA components (HLA tetramer)
Why use an HLA tetramer
Increased avidity
It is coupled to a fluorochrome and identified by flow cytometry
What is this approach used for
EBV
Cytotoxicity assay
Examine specific lysis by CTL and killing by NK cell
How does cytotoxity assay work
Incubate together te effector cells and target cells and measuring damage to the targets
The appropriate MHC matched target cell must be used
The target cells are labeled with sodium chromare (51Cr)
Targets and effectors incubated for 4-5 hours
If target cells are damaged by the effectors CR51 is released fromt he cytoplasm into the culture fluid
Can use other radioactive thing besides CR51
So…Dc goes to nodes with viral antigens, but must find a T cell with the TCR that first the peptide MHC complex . How many T cells can a dc cell contact per hour
5000
How does the lymph node get more naive T cells for a DC
Upregulate adhesion molecules on high endothelial venule structures to draw in more naive T cells
SWELLING AND TENDERNESS
What happens when a tCR-pMHC interaction occurs
T cell stops migrating and becomes more tightly adhered to DC and traduced by CD3
THIS IS CALLED SIGNAL 1
Signal 1
Peptide-MHC and tCR interaction is transduce by CD3 complex
Is signal 1 sufficient to activate naive T cell
No
What is signal 2
Co stimulation
What are the costimulatory molecules on the DC
CD80 and 86
Immature DC have _ levels of CD80/86 and mature DC have _ levels of CD80/86
Low
Upregulated
What do CD80/86 onthe dendritic cell bind to
CD28 on the T cell
What does binding of CD80 and 86 to CD28 lead to
CD 28 cytoplasmic domain binds a phosphoinositide 3 kinase to initiate an activation cascade leading to transcription of the Il-2 and Il-2 receptor genes
What is Il-2 also known as
T cell growth factor
What does Il-2 do
Major cytokine responsible for t lymphocyte activation and proliferation
Describe the il-2 autocrine loop
Receipt of an appropriate activation signal by a T cell results in massive upregulation of production of both the cytokine and its receptors so that Il-2 can feed back activating signals through its receptor
Il-2 paracrine
Activate nearby T cells in a paracrine fashion
Il-2 on B cells
Development of B cells
IL-2 is part of a family of interleukins (il-4, 7, 9, 15, 21) that share a common receptor component. What is t
Gamma chain
What are the three chains of the I’ll-2 receptor
A, b, y
What is the minimal receptor configuration for signal transduction of IL-2
IL-2Rby
IL-2Ra (CD25)
treg
Are dependent on il-2 for differentiation and function
Il-2 pathway is a target of drugs. What do they do
Dampen down the immune system either by interfering with signalling (ciclosporin, tacrolimus) or using monoclonal antibodies against CD25(daclizumbab)
How does the il2 lead to cell proliferation
Bind a chain(traps it) transfer of il2 to the by dimer or the receptor which allows for internalization leading to cell proliferation
What does a requirement for signals 1 and 2 mean
Only highly activated dc have necessary power to activate naive T cells
Adaptive system relies on innate
Fail safe mechanism
Danger hypothesis
DC must receive appropriate activation signals from athogen
Without element of danger provided by a CD PRR interacting with a pathogen, PAMP, there will be insufficient signalling to activate a naive T cell
Signal 3
Cytokines from DC that polarize the T cell response
What dictates the quality of signal 3
Nature of Dc
The TH1 polarizing cytokine ___, os critical at this state for driving a CD4 T cell response dominated by ___
Il-12
IFN-y
What conditions favor TH2 response
Less Il-12 and more Il-4
What conditions favor TH17
Il-23, 6, tgfb
Treg conditions
TGFb and Il-10
What produces Il-10
Immature DC
——fail safe mechanism to control exercised DC
If there is antigen presentation by an immature CD that makes IL-10 (in absence of PRR-PAMP) then the T cell response is what
Default pathway TREGS
th1, TH2, TH17, Treg all have what marker
CD4
What does TH1 produce
IFN-y, il-2, tnfa
What does th2 produce
4, 5, 13
What does th17 produce
Il-17
What does treg produce
Il-10, tfgb
Major role of th1
Organize killing of bacteria, fungi and viruses
Activate macrophages to kill intracellular bacteria and instruct ctl response
Major role of TH2
Organize killing or parasites by recruiting eosinophils, promote antibody responses
Major role of th17
Not yet fully understood
Capable of recruiting cells and damaging targets
Major role of treg
Regulate inflammation
What transcription factors activated by TH1
T-bet
STAT-4
What transcription factors activated by TH2
GATA-3
STAT-6
What transcription factors activated by TH17
RORyT
What transcription factors activated by Treg
FOXP3
What does il-4, produced by th2, do?
Potent stimulation for B cell switching to IgE
Parasitic and allergies
Growth factor for TH2
Inhibitory cytokine for th1 differentiation
What does Il-4 inhibit
TH1
Immunological synapse
Interchange is highly organized into two zones by the immunological synapse
What is the inner part of the synapse
Central supramolecular complex or cSMAC
It is composed of TCRs pairing with peptide MHC, CD28-CD80 and expression of PKC
The cSMAC forms a bulls eye with the peripheral SMAC, pSMAC. What is in the c and p
C-150 TCR
P-adhesion molecules like LFA-1 and ICAM-1
What are the 2 main themes overlying the intracellular processes of lymphocyte activation
Transduction and amplification
What does transduction and amplification lead to
Transcription factors and DNA binding proteins generation
Initiating process of transcription and translation
What do intracellular events involve
- Early generation of enzymes capable of protein tyrosine phosphorylation
- Early activation of the phosphatidylinositol membrane pathway , which leads to generation of high levels of intracellular calcium
- Recruitment of adaptor proteins which act as signal relays
- Cascading of signals through molecular pathways 5. Activation of nuclear transcriptional events
Important amplification is also supplied through enzyme activities in the accessory molecules of t and B cells. What are they
T-cd4, 8.
B-cd19-21-81 complex, cd20, 22, 40
Cd45
Appears to supply critical amounts of tyrosine phosphatase activity to both cell types
Do the TCR and BCR complex have intrinsic PTK activity
No
Taking T cell activation, it is known that cd3 complexes contain numerous distinctive repeating immunoreceptor tyrosine based motifs (ITAMs) that become phosphorylation by what
Src family kinases (Fyn, Lck)
What does phosphorylation of ITAMs by Fyn and Lck cause
Sites for ZAP-70 to bind which becomes activated
Down stream events of activated Zap-70 bound to ITAMs on CD3
Intracellular second meessengers(calcium PKC) Adaptors Lat (linker for activated T cell) that recruit other signalling molecules together into multimlecular complexes that relay signals further downstream
As the cascade of kinase activities approach the nucleus,there are different pathways. What is the calcineurin pathway
Activates calcineurin, a calcium dependent protein phosphatase, which dephosphorylates a nuclear transcription factor present int he cytoplasm, NF-ATc, which is thus enabled to translocation from the cytoplasm to the nucleus and there to initiate transcription of the IL-2 gene in concert with similar nuclear transcription factor (NF-ATn).
Further signalling events are provided by ligation of CD28 by CD80/86 on DC surface. What does this do
Important for IL2 production
What other important transcription factors are promoted at this stage
NF-kb and AP-1
What are the subgroups of helper T cells
TH1 and TH2
*based on cytokine production
Il-5
From TH2
And mast
Promotes B cell growth and immunoglobulin production, stimulate eosinophil, and activate mature eosinophils to kill parasitic worms
Il-6
From T cells and apc(macrophages and DC)
Stimulated by il-1 and tnf-a
Acute phase response to inflammation
Induces liver to synthesize plasma proteins that are involved in acute phase reactions such as clotting a complement factors and c reactive protein .
Potent effects on B cell differentiation, growth and immunoglobulin class switching . Also dives differentiation of th17
Il10
Immunosuppressive
Made by treg, macrophages, dc, and some B cells
Inhibits production of pro inflammatory cytokines like tnfa and il1 and down regulates expression of MHC and co stimulators molecules
What is the effect of il10 on B cell
Stimulators
If you
Homodimer from th1, cd8, and NK cells
Antiviral
Activates macrophages(increase metabolic and phagocytosis and killing)
Increase MHC class I molecules and MHCII
Favors TH1 and B cell differentiation
FAVOR IgG
TGIF-B1
Immunosuppressive
From treg and macrophages and dc
Reduced proliferation of t and B cells, reduced cytokine release and inhibition of APC function
I’ll-12
From activated DC
Induces naive T cell to th1
The balance between il12 and il4 determines what
Whether cell becomes th1 or TH2
What does il12 promotes
IFNy and TNFa and activates NK cells
What do Th17 secrete
Il6, 8 and GM-CSF
What murine versions of disease is th17 important in
RA and MS
Net result of TH2 activation
Activation and expansion of B cells
Their differentiation along different pathways of antibody production memory T cell will
B cell presents antigen on what
MHCII molecule
What does B cell with antigen on MHCII molecule activate
TH2
What does TH2 secrete
Il2, 4, 5
What do il2, 4, and 5 do
Activate and expand b cellls
TH2 secretes il2, 4, 5, 6
IgM B cells
Th2 secretes il2, 4, 6, IFn-y
IgG
Th2 secretes il-4
Get IgE
What do th1 cell activate
Macrophages to kill organisms that they have internalized and presented
How do cd4 T cells also influence dc during antigen presentation
Cd40-cd40l
What is cd40-cd40l important for
Licensing DC for activation of other cells, especially naive cd8 cells
The induction of a ctl response is dependent upon ___ T cells to provide help in the form of activation stimuli and dc licensing
Cd4
Can cd8 T cells leaving the thymus lyse target cells
No, but they have a tcr
What activates a pre ctl
Dc and cd4 T cells
The cd4 and cd8 need to cluster in the same dc region in order for sufficient activation stimuli to be generated
This also ensures that the cd8 T cell is activated against a target for which there is a cd4 T cell response
Cd4 naive T cells are only activated by dc when danger signals are present. What does this ensue
Ctl generation is restricted to important targets such as viruses, rather than self antigens
What cytokines stimulate ctl
Il2 mainly
Also ifny
Following activation, the CTL must prepare the machinery required to lyse target cells. What do ctl use to lyse target cells
Cytotoxic granule proteins
Toxic cytokines
Death inducing surface molecules
Cytokines granule proteins are present in ____ structures proximal to the membrane
Lysosomal
Upon activation of the ctl by a target bearing appropriate peptide MHC, there is ___ of granule release organized by the cell cytoskeleton onto the target cell surface
Polarization
One type of cytotoxic granule protein is called ____, which forms membrane pores and is very reminiscent of the membrane attack complex of complement c5-c9
Perforin
At the same time, ctl granules containing ____ are relapsed
Granzymes
The perforin pores aid into e arrival of granzymes into the cytoplasm where they activate a cytoplasmic protein ____
Caspase 3
What does active caspase 3 do
Cascade leads to programmed cell death also called apoptosis
The second killing mechanism is cytokinee released directed onto the cell surface. IFNy and TNFa do what
Induce cell damage
IFNy
Direct antiviral activity, which may be of local importance when a viral infected cell is lyse and visions released
Tnfa
Toxic to a range of cell types
The third mechanism of inducing cell death relies upon the surface expression of death inducing molecules by the ctl, and engagement of the appropriate ligand onthe target cell surface. Like what
Fas ligand (FasL), which binds Fas on target cells. Fas contains an intracellular death domain which leads to apoptosis via caspase activation
What must we do with lymphocytes with an antigen receptor that could indeed by self destructive
Weeded out or tightly controlled
What happens if you remove the thymus
Autoimmune
What surface expression is on Treg
CD25 (il2 receptor a chain). Foxp3
What do treg cells lack
CD127 (il7 receptor).
Treg describe in totality
CD4 CD25 CD127lo Foxp3 CTLA4
What do treg do
Cell to cell contact
Secrete il10 and tgfb
Ctla4 surface expression
What does ctla4 do
Binds to cd80/86 co stimulators molecules with a higher affinity than cd28, delivering inhibitory signal to the T cell and thus regulating immune suppression
What percent of T cells in blood are treg
5-10%
Tr1
Treg that produces il10
Another subset of treg
Tgfb
Bystander suppression
Secrete tgfb but once activated they can regulate any surrounding cells, including those specific from the same antigen as well as others in the vicinity
Linked suppression
Is regulated cell is not he same apc and is responding to the same or a related antigen
IPEX
Immune dysregulation, polyendocrinopathy, enteropathy, enteropathy, x linked syndrome
Defective foxp3
For people with IPEX, what happens if you have a defective Foxp3
Severe inflammatory processes leafing to gut and skin disease within the first year of life
Bc of unchecked auto regulatory cells
Most notably people with IPEX develop what
Type 1 diabetes
From unchecked autoreactive T cells due to the absence of thymus derived islet reactive tregs
Are nk cells bone marrow derived lymphocytes
Yup
NK cells are able to mediate their effector function ___ in the absence of previous known sensitization to that target
Spontaneously
Do NK cell receptors undergo somatic recombination
No
Why are NK innate immune system
Lack of requirement for sensitization and the absence of gene rearrangement to derive receptors for target cells
How identify nk
CD16, CD56
CD3-, TCR-
What do nk cells do
Kill abnormal host cells, typically cells that are virtue infected or tumor cells
How do nk kill cells
Exocytosis of the lyric proteins such as perforin and granzymes and expression of FalL
Nk secrete ifny and tnfa what does this do
Mediate cytotoxic effects (upregulation of MHC molecules on target cells) an activate other components of the innate (DC) and adaptive system (T cell)
The interaction between nk and the adaptive immune system is two directional. Describe
Nk cell function can be influenced by b and T cells.
Nk express cd16 and low affinity receptor for igG(FcyIIIA)
Nk can kill igG coated target cells in a process termed antibody dependent cellular cytotoxicity
Nk cells use inhibitory receptors on their surface to survey targets for the presence of mhcI. If molecules are present what happens
Inhibition of activation
What are the inhibitory receptors called on nk cells
KIRS
Killer cell immunoglobulin like receptors
Are KIR polymorphic
Highly
Ligand HLA-C
Receptor on nk cell
KIR2DL1
HLA-B ligand
Receptor on nk cell
KIR3DL1
ligand HLA-A molecules
Receptor on nk cell
KIRDL2
HLA-E ligand molecule
Receptor on nk cell
NKG2A
Ligand IgG
Receptor on nk cell CD16(low affinity receptor for IgG)
ligand MHCI chain related A (MICA)
Receptor on nk cell
NKG2D
HLA-C ligand
Receptor on nk cell
KIR2DS1
Once contact is made, adhesion is important and is predominantly mediated by what
LFA1:ICAM1 interactions
What do LFA1:ICAM1 interactions cause
Polarize NK cell onto its target and direct the release of granules and cytokines
MICA
Receptor induced under conditions of cellular stress (infection or neoplasticism transformation)
What is viruses can avoid CTL
Nk cells can kill. They sense reduced number of mhcI
Tumors that escape immune surveillance
Nk cell see low MHC expression
NK cellls are a small population of cells that resemble lymphocytes morphological but form a separate lineage from t and B cells
Nk cells kill tumour cells and virally infected cells without the need for prior sensitization
Nk cells secrete cytokines (mainly ifny) which promote a cellular immune response, activating phagocytosis cells and recruiting T cells
Nk cells are activated by the cytokines ifny, il2, il12 and have two mechanisms of killing targets. On on , target cells are bound by IgG antibody, for which the NK cell has a receptor. In the second, cell-cell contact with the target is required during which the balance of activating and inhibitory receptor signalling determines the outcome.
