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Immunology > Cellular Immune Response II: T Lymphocytes, Antigen Presentation And NK Cells > Flashcards

Cellular Immune Response II: T Lymphocytes, Antigen Presentation And NK Cells Flashcards

1
Q

lymphocytes are responsible for antibody production and graft rejection

A

Ok

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2
Q

T cells are generated from precursors in the ___ ___

A

Bone marrow

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3
Q

In the bone marrow rearrangement of the genes produces what

A

Receptor for the antigen

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4
Q

Then t lymphocytes leave the bone marrow and go to lymph nodes as __, or ___

A

Naive immature

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5
Q

Properties of a naive T cell

A
  • functional rearrangement and expression of their surface receptors for an antigen
  • a reduced or absent tendency to recognize self antigens
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6
Q

Where do naive T cells become activated

A

In lymph nodes when antigens are presented to them as short peptides on MHC

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7
Q

The only APC capable of activating naive T cells is ___

A

DC

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8
Q

After T cell activated get functional polarization. What is functional polarization

A

T cell takes on a particular set of tastes that promote the adaptive immune response , effector or regulatory functions
Like organizing B cell responses

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9
Q

Where is the pre T cell

A

Bone marrow

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10
Q

Where is there selection of T cells with appropriately rearranged receptors for antigen

A

Thymus

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11
Q

Where are naive T cells

A

Lymph node

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12
Q

Where fo T cells encounter antigen bearing DC

A

Lymph node

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13
Q

Where do T cells carry out effector functions

A

Peripheral tissue

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14
Q

Where are memory T cells

A

Lymph node

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15
Q

CD3 complex

A

On T cell

Collection of molecules that transduce activation signals

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16
Q

5% of TCR are what

A

Y and delta

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17
Q

What are they two receptor options for tCr

A

Ab or gammadelta

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18
Q

What are the two types of T cells

A

CD4 and CD8

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19
Q

Are there more cd4 or cd8

A

1/3 8

2/3 4

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20
Q

Host helper cells have what receptor

A

Ab

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21
Q

Most cytotoxic have what receptor

A

Gammadelta

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22
Q

T cell surface markers

A

TCR and CD3

All T cells are thymus derived

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23
Q

CD4

A

On helper T cells 66% of all T cells

Interact with MHCII

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24
Q

CD8

A

On cytotoxic lymphocytes
33% of T cells
Interact with antigen presentation by MHC class I molecules

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25
Q

___ T cells are lost in HIV

A

Cd4

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26
Q

Flow cytometry

A

For T cells

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27
Q

Cell subset quantification exploit three items:

A
  1. Existence of a surface molecules
  2. Monoclonal antibody specific for the molecule
  3. Chemicals called fluorochromes that fluoresce at a particular wavelength when exposed to an excitatory light source
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28
Q

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

A

Green orange then red respectively

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29
Q

The cells labeled with fluochrome are exposed to a laser, viewed and counted. What technique is this done by

A

Flow cytometry

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30
Q

Basic flow cytometry

A
  1. Cells identified by the way they scatter light in the forward direction(dependent on size) and at 90 degrees (dependent on granules in cytoplasm)
  2. Machine analyzes whether a particular cell has been bound by the monoclonal antibody
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31
Q

High light scattered at 90 degrees

A

Granular cell, neutrophil

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32
Q

Low or no light scatter at 90 degrees

A

Angular cell like a lymphocyte

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33
Q

High light scattered forward

A

Large cell, like a neutrophil

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34
Q

Low or no light scatter forward

A

Small cell like a lymphocyte

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35
Q

High fluorescence from labeled antibodies

A

Cell stained, like a B cell

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36
Q

Low or absent fluorescence emission from labeled antibodies

A

Cell not stained like a T cell

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37
Q

How can DC help prevent reactions against self

A

Only guides responses when danger signals are present , could give stop and go advice when initiating immune response

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38
Q

What if T cells generated tcr that bound with such high affinity that they do not require dc to become activated

A

Autoimmunity

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39
Q

Pre T cells

A

No surface markers can not be identified as T cells and they go to the thymus

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40
Q

What are precursor T cells called in the thymus

A

Thymocytes

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41
Q

How long does thymic education for a cell emerging into the periphery take

A

3 weeks

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42
Q

How long is a thymocytes in the thymus when not destined for selection

A

3.5 days

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43
Q

Facts about mature T cell

A

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

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44
Q

Describe path of pre T cell from bone marrow to thymus

A

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

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45
Q

Thymic education

A

T cell acquired tools of their trade in the thymus

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46
Q

There is an extensive thymocyte death, only _% of precursor cells entering the thymus leave as mature cells

A

1

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47
Q

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

A

Yup

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48
Q

Three basic elements of thymocyte selection

A
  1. Discard all tcr that are incapable of interacting with self MHC molecules
  2. Discard al tcr with dangerously high affinity for self MHC (negative selection
  3. Select tcr that are between these two extremes (positive selection)
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49
Q

T cell negative selection

A

Get rid of undesirable

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50
Q

T cell positive selection

A

Keep good quality

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51
Q

The arriving thymocyte migrates to the ___ of the thymus and undergoes twenty fold expansion

A

Cortex

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52
Q

When the pre T cell arrives at the thymus, is there a T cell receptor, cd4 or cd8?

A

Nope

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53
Q

Double negative stage

A

No cd4 or cd8

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54
Q

For the DN thymocyte, do tcrb or tcra chains rearrange first

A

Tcrb

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55
Q

At this stage, the tcrb chain pairs with an invariant ___-

A

Tcr a chain that assists signalling through cd3 complex

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56
Q

If the thymocyte fails at the first checkpoint, it will die. What is the thymocyte at the first checkpoint

A

Thymocyte in thymus with tcrb and an invariant pre tcra chain with cd3
This checkpoint looks for successful productions of tcrb

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57
Q

If it passes the first checkpoint(good tcrb) what will the DN thymocyte express next

A

Both CD4 and CD8 and rearrange the tcra chain

Now there is an tcrab dimer

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58
Q

What is a cthymocyte called that expresses both CD4 and CD8

A

Double positive (DP)

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59
Q

What does the thymocyte look like at the second checkpoint

A

Has TCRab dimer, and CD4 and CD8

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60
Q

The DP loses one Cd4 or CD8 and becomes what

A

Single positive. SP4 SP8

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61
Q

If cells are separated from an active thymus, stained for cd4 and cd8. What will you see

A

Different DN, DP and SP stages

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62
Q

What happens when SP4 or SP8 interact with mTEC

A

MHC

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63
Q

90-95 % of thymocytes fail in a 3-4 day window (SP) and die. What is this death called

A

Death by neglect

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64
Q

Where does death by neglect happen

A

Thymic cortex and

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65
Q

What is death by neglect in the thymic cortex mediated by

A

Cortical thymic epithelial cells (cTEC)

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66
Q

SP cells migrate towards the thymic medulla fromthe cortex, where they interact with ____

A

Medullary TEC (mTEC)

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67
Q

What do mTEC do

A

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

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68
Q

AIRE gene

A

Transcription factor from mTEC

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69
Q

Humans deficient in AIRE

A

Syndrome in which multiple manifestations of self reactive T cells

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70
Q

So. MTECs display peripheral self antigens to enable what

A

Deletion of any SP T cells processing TCRs capable of very strong binding too self

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71
Q

What happens to SP T cells that have strong binding to self antigens when presented by MHC

A

Actively deleted, negative selection , on T cells with high avidity for self antigens

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72
Q

A feroprotein is presented my mTEC. Where is it from

A

Liver

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73
Q

Where is serum amyloid P

A

Liver

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74
Q

Where is trypsin

A

Pancreas

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75
Q

Where is insulin

A

Islet of Langerhans

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76
Q

Where is glutamic acid decarboxymlase

A

Islet of langerhans

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77
Q

Where is somatostatin

A

Islet of langerhan

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78
Q

Where is crystalline

A

Eye

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79
Q

Where is retinal s antigen

A

Eye

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80
Q

Where is thyroglobulin

A

Thyroid

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81
Q

How long are thymocytes in the thymus being educated

A

3 weeks

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82
Q

Qualifications for thymocyte to survive

A

Productive rearrangement and expression of TCRabTCR capable of moderate interaction with MHC
Affinity for self antigens cant be too high

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83
Q

What happens after positive selection

A

T cell goes to periphery where as a naive T cell it resides in the lymphatic system

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84
Q

What do naive T cells do in the lymphatic system

A

Recirculate between nodes and blood

Ready for dc to represent antigens

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85
Q

What important marker is on CD4 T cells for B cell activation

A

Cd40L (CD154)

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86
Q

What does cd40l on T cell bind to

A

Cd40

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87
Q

What are th major functions of T cells Cd4

A

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

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88
Q

Is CD3 required for T cell function

A

Yes

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89
Q

What are some accessory molecules-important additional signals and interactions

A

CD3, 4, 8

CD28

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90
Q

In clinical , what are monoclonal antibodies able to identify

A

Different T cell associated molecules and can be used to subdivide the total T cell population into T cell subsets

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91
Q

What is the CD3 complex analagous to

A

B cell receptor complex

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92
Q

What does CD3 do

A

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

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93
Q

The antigen receptor has no signalling properties like the B cells. How does cd3 transmit signal

A

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

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94
Q

The CD3 complex is composed of five different transmembrane protein chains denoted what

A

Gamma, delta, epsilon, zeta and eta

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95
Q

One epsilon chain associates non covalently with a delta chain and this complex lies adjacent to the a chain of the TCR

A

Ok

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96
Q

An epsilon gamma complex associated with the b chain

A

Yup

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97
Q

Nearby there is a zeta zeta homodimer (%) or a zeta eta heterodimer (%)

A

90 10

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98
Q

What are cd4 and cd8

A

Accessory molecules in T cell function

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99
Q

Describe cd4

A

Transmembrane glycoproteins monomer
Member of immunoglobulin supergene family
Has 4 immunoglobulin like domains

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100
Q

What does cd4 do

A

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

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101
Q

___ is the cellular receptor for HIV

A

CD4

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102
Q

Describe the cd8

A

Disulphide linked dimer having a single immunoglobulin like domain
A and b chains

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103
Q

What does cd8 do

A 
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
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104
Q

B cells see free antigens. Do T cells

A

No MHC restricted

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105
Q

What kind of peptides are presented to cd8

A

Internal antigens like viruses

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106
Q

What kind of peptides are presented to cd4

A

External antigens from microbes

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107
Q

Proliferation assay

A

Lymphocytes separated from whole blood (densities)

Blood layered onto a solution of fixed density then centrifuges

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108
Q

List order of cells after centrifuge from top to bottom (least dense to most dense)

PBMC preparation

A 
Light cells(platelets)
Moderate density cells (lymphocytes, monocytes)
Dense cells (RBC, granulocytes )
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109
Q

Selected populations can be further purified using monoclonal antibodies coated with magnetic beads

A

Yup

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110
Q

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

A

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

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111
Q

Describe the exogenous pathway

A

Pinocytosis(DC), receptors for antigen (mannose receptor and DC-sign

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112
Q

Anter an antigen is internalized by a B cell in the exogenous pathway, where does it go

A

Late endosomes

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113
Q

What happens in late endosomes

A

Fuse with lysosomes
Low pH
Antigen degradation

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114
Q

How does an antigen get into B cell

A 
Pinocytosis (DC cell)
Antibody (B cell)
Complement receptor
Fc receptor 
Mannose receptor
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115
Q

APCs continually make ____ which is assembled in the ER

A

MHCII

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116
Q

Transcription and translation and processing of MHCII is ____ when AC are activated

A

Upregulated

*parallels DC and PRR

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117
Q

Newly formed MHCII travel via the __ to come in contact with late endosomes

A

Golgi

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118
Q

The antigen binding grow of MHCII is protected throughout irs journey through the cytoplasm from accepting peptide antigens by the presence of ___ ___ (_)

A

Invariant chain (li)

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119
Q

What does Ii chain do

A

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
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120
Q

What part of the Ii chain occupies the MHC groove and prevents any other self peptide from binding

A

CLIP region (class II associated invariant chain peptide)

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121
Q

Where does peptide load MHCII

A

Group of vesicles in a late endosome compartment termed MIIC (MHC class II compartment)

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122
Q

What happens in the MIIC

A

Ii chain is released and a new peptide from exogenous antigens is inserted into the groove

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123
Q

What molecules catalyst loading of peptide into MHCII and losing Li

A

HLA-DM in APD

In B cell an additional HLA-DO

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124
Q

In the late endosome/lysosomes what is degreasing the protein

A

Low pH, AEP, GILT, cathespins

125
Q

GILT

A

Gamma inducible lysosomal thiol reductase

Cleaves disulphide bonds

126
Q

AEP

A

Asparaginyl endopeptidase

Cleaves asparagina (N) residues

127
Q

Together what do GILT and AEP accomplish

A

Unfolding! Antigens relax after disulphide bonds are cleaved or removal of N

128
Q

Cathespins

A

Enzymes with broad specificity that cleave at both ends of proteins

129
Q

Describe endogenous pathway

A

Peptides from fragments of endogenously synthesized proteins

130
Q

Where does antigen peptide loading take place of MHCI

A

In the ER, where B2 microglobulin and MHCI heavy chains assembled

131
Q

The assembly of a peptide loaded MHCI molecule depends upon 3 components

A

Heavy chain, B2 microglobulin and calnexin

132
Q

What is calnexin

A 
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
133
Q

Calreticulin

A

Chaperone molecule that ensures that the a heavy chain and B2 microglobulin are stable until antigenic peptide is loaded

134
Q

How do peptides arrive in the ER int he endogenous pathway

A 
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
135
Q

Tapasin

A 
TAP transporters are kept in close proximity to the waiting class I molecule by. Tapasin
Also increases stability of intermolecular interactions
136
Q

What is the peptide loading complex made of

A

4 calreticulin
4 tapasin
TAP1, TAP2

137
Q

What does calnexin do

A

Chaperone for protecting empty groove

138
Q

What does calreticulin fo

A

Chaperone for maintaining stability in absence of peptide (MHCI)

139
Q

TAP1 and TAP2

A

Transportation into ER and editing of cytoplasmic peptides

140
Q

Tapasin

A

Brings empty classs I molecule close to loading site

141
Q

Proteosome

A

Generates peptides for loading

142
Q

Proteosome

A

Large complex of proteases with multicatalytic capabilities

Big enoug to see on electron microscopy

143
Q

What does proteosome look like on electron microscopy

A

Cylinder shape like a cotton reel

4 rings and 7 cylinders with a hollow core

144
Q

What cells does proteosome process

A

Ones that have been tagged with ubiquitin

145
Q

What would a protein by ubiquinated

A

Surplus of misfiled

146
Q

PSMB8, PsMB9

A

Immunoproteosome, only found in dendritic cells (also encoded on MHCII region)

147
Q

TAP and PSMB are found on MHCII region gene. What does this mean

A

Influence of one region of MHC on the other

148
Q

How do viral proteins synthesized in the Er load mhcI

A

Retrograde translocation

149
Q

Retrograde translocation

A

ER associated degradation (ERAD) stayed

150
Q

Subversion of the immune system

A

Microorganisms evolve mechanisms to evade the immune system

151
Q

Strep pneumonia and Neisseria meningitidis

A

Complex capsular carbohydrates that prevent access of antibodies and complement to bacterium

152
Q

Kaposi Sarcoma associated herpes virus

A

Tumor of lymphatic vessel endothelium

Genome has several viral homologues of human immune modulator genes (il-3, 6)

153
Q

RNA viruses

A

High mutational frequencies

154
Q

Herpes simplex and its encoded ICP47

A

Cytotoxic protein that binds TAP1/2 diners to prevent peptide binding and entry into the ER lumen

155
Q

Cross presentation

A

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

156
Q

How do viral proteins undergo retrograde translocation

A

With a protein conducting channel, Sec61

157
Q

What does retrograde translocation allow

A

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

158
Q

How do we activate T cells artificially in the lab (al T cells)

A

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)

159
Q

How do we activate a specific T cell artificially

A

Specific antigen of peptide epitope is added to cultures

160
Q

How do we detect cytokine responses of T cells

A

Elisa
Flow cytometry-detect inside cell
Pcr-detect cytokine specific mRNA transcripts quantified by PCR

161
Q

What new method is used to quantify antigen specific T cells

A

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)

162
Q

Why use an HLA tetramer

A

Increased avidity

It is coupled to a fluorochrome and identified by flow cytometry

163
Q

What is this approach used for

A

EBV

164
Q

Cytotoxicity assay

A

Examine specific lysis by CTL and killing by NK cell

165
Q

How does cytotoxity assay work

A

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

166
Q

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

A

5000

167
Q

How does the lymph node get more naive T cells for a DC

A

Upregulate adhesion molecules on high endothelial venule structures to draw in more naive T cells
SWELLING AND TENDERNESS

168
Q

What happens when a tCR-pMHC interaction occurs

A

T cell stops migrating and becomes more tightly adhered to DC and traduced by CD3
THIS IS CALLED SIGNAL 1

169
Q

Signal 1

A

Peptide-MHC and tCR interaction is transduce by CD3 complex

170
Q

Is signal 1 sufficient to activate naive T cell

A

No

171
Q

What is signal 2

A

Co stimulation

172
Q

What are the costimulatory molecules on the DC

A

CD80 and 86

173
Q

Immature DC have _ levels of CD80/86 and mature DC have _ levels of CD80/86

A

Low

Upregulated

174
Q

What do CD80/86 onthe dendritic cell bind to

A

CD28 on the T cell

175
Q

What does binding of CD80 and 86 to CD28 lead to

A

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

176
Q

What is Il-2 also known as

A

T cell growth factor

177
Q

What does Il-2 do

A

Major cytokine responsible for t lymphocyte activation and proliferation

178
Q

Describe the il-2 autocrine loop

A

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

179
Q

Il-2 paracrine

A

Activate nearby T cells in a paracrine fashion

180
Q

Il-2 on B cells

A

Development of B cells

181
Q

IL-2 is part of a family of interleukins (il-4, 7, 9, 15, 21) that share a common receptor component. What is t

A

Gamma chain

182
Q

What are the three chains of the I’ll-2 receptor

A

A, b, y

183
Q

What is the minimal receptor configuration for signal transduction of IL-2

A

IL-2Rby

184
Q

IL-2Ra (CD25)

A

treg

Are dependent on il-2 for differentiation and function

185
Q

Il-2 pathway is a target of drugs. What do they do

A

Dampen down the immune system either by interfering with signalling (ciclosporin, tacrolimus) or using monoclonal antibodies against CD25(daclizumbab)

186
Q

How does the il2 lead to cell proliferation

A

Bind a chain(traps it) transfer of il2 to the by dimer or the receptor which allows for internalization leading to cell proliferation

187
Q

What does a requirement for signals 1 and 2 mean

A

Only highly activated dc have necessary power to activate naive T cells
Adaptive system relies on innate
Fail safe mechanism

188
Q

Danger hypothesis

A

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

189
Q

Signal 3

A

Cytokines from DC that polarize the T cell response

190
Q

What dictates the quality of signal 3

A

Nature of Dc

191
Q

The TH1 polarizing cytokine ___, os critical at this state for driving a CD4 T cell response dominated by ___

A

Il-12

IFN-y

192
Q

What conditions favor TH2 response

A

Less Il-12 and more Il-4

193
Q

What conditions favor TH17

A

Il-23, 6, tgfb

194
Q

Treg conditions

A

TGFb and Il-10

195
Q

What produces Il-10

A

Immature DC

——fail safe mechanism to control exercised DC

196
Q

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

A

Default pathway TREGS

197
Q

th1, TH2, TH17, Treg all have what marker

A

CD4

198
Q

What does TH1 produce

A

IFN-y, il-2, tnfa

199
Q

What does th2 produce

A

4, 5, 13

200
Q

What does th17 produce

A

Il-17

201
Q

What does treg produce

A

Il-10, tfgb

202
Q

Major role of th1

A

Organize killing of bacteria, fungi and viruses

Activate macrophages to kill intracellular bacteria and instruct ctl response

203
Q

Major role of TH2

A

Organize killing or parasites by recruiting eosinophils, promote antibody responses

204
Q

Major role of th17

A

Not yet fully understood

Capable of recruiting cells and damaging targets

205
Q

Major role of treg

A

Regulate inflammation

206
Q

What transcription factors activated by TH1

A

T-bet

STAT-4

207
Q

What transcription factors activated by TH2

A

GATA-3

STAT-6

208
Q

What transcription factors activated by TH17

A

RORyT

209
Q

What transcription factors activated by Treg

A

FOXP3

210
Q

What does il-4, produced by th2, do?

A

Potent stimulation for B cell switching to IgE
Parasitic and allergies
Growth factor for TH2
Inhibitory cytokine for th1 differentiation

211
Q

What does Il-4 inhibit

A

TH1

212
Q

Immunological synapse

A

Interchange is highly organized into two zones by the immunological synapse

213
Q

What is the inner part of the synapse

A

Central supramolecular complex or cSMAC

It is composed of TCRs pairing with peptide MHC, CD28-CD80 and expression of PKC

214
Q

The cSMAC forms a bulls eye with the peripheral SMAC, pSMAC. What is in the c and p

A

C-150 TCR

P-adhesion molecules like LFA-1 and ICAM-1

215
Q

What are the 2 main themes overlying the intracellular processes of lymphocyte activation

A

Transduction and amplification

216
Q

What does transduction and amplification lead to

A

Transcription factors and DNA binding proteins generation

Initiating process of transcription and translation

217
Q

What do intracellular events involve

A
  1. Early generation of enzymes capable of protein tyrosine phosphorylation
  2. Early activation of the phosphatidylinositol membrane pathway , which leads to generation of high levels of intracellular calcium
  3. Recruitment of adaptor proteins which act as signal relays
  4. Cascading of signals through molecular pathways 5. Activation of nuclear transcriptional events
218
Q

Important amplification is also supplied through enzyme activities in the accessory molecules of t and B cells. What are they

A

T-cd4, 8.

B-cd19-21-81 complex, cd20, 22, 40

219
Q

Cd45

A

Appears to supply critical amounts of tyrosine phosphatase activity to both cell types

220
Q

Do the TCR and BCR complex have intrinsic PTK activity

A

No

221
Q

Taking T cell activation, it is known that cd3 complexes contain numerous distinctive repeating immunoreceptor tyrosine based motifs (ITAMs) that become phosphorylation by what

A

Src family kinases (Fyn, Lck)

222
Q

What does phosphorylation of ITAMs by Fyn and Lck cause

A

Sites for ZAP-70 to bind which becomes activated

223
Q

Down stream events of activated Zap-70 bound to ITAMs on CD3

A 
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
224
Q

As the cascade of kinase activities approach the nucleus,there are different pathways. What is the calcineurin pathway

A

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).

225
Q

Further signalling events are provided by ligation of CD28 by CD80/86 on DC surface. What does this do

A

Important for IL2 production

226
Q

What other important transcription factors are promoted at this stage

A

NF-kb and AP-1

227
Q

What are the subgroups of helper T cells

A

TH1 and TH2

*based on cytokine production

228
Q

Il-5

A

From TH2
And mast
Promotes B cell growth and immunoglobulin production, stimulate eosinophil, and activate mature eosinophils to kill parasitic worms

229
Q

Il-6

A

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

230
Q

Il10

A

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

231
Q

What is the effect of il10 on B cell

A

Stimulators

232
Q

If you

A

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

233
Q

TGIF-B1

A

Immunosuppressive
From treg and macrophages and dc
Reduced proliferation of t and B cells, reduced cytokine release and inhibition of APC function

234
Q

I’ll-12

A

From activated DC

Induces naive T cell to th1

235
Q

The balance between il12 and il4 determines what

A

Whether cell becomes th1 or TH2

236
Q

What does il12 promotes

A

IFNy and TNFa and activates NK cells

237
Q

What do Th17 secrete

A

Il6, 8 and GM-CSF

238
Q

What murine versions of disease is th17 important in

A

RA and MS

239
Q

Net result of TH2 activation

A

Activation and expansion of B cells

Their differentiation along different pathways of antibody production memory T cell will

240
Q

B cell presents antigen on what

A

MHCII molecule

241
Q

What does B cell with antigen on MHCII molecule activate

A

TH2

242
Q

What does TH2 secrete

A

Il2, 4, 5

243
Q

What do il2, 4, and 5 do

A

Activate and expand b cellls

244
Q

TH2 secretes il2, 4, 5, 6

A

IgM B cells

245
Q

Th2 secretes il2, 4, 6, IFn-y

A

IgG

246
Q

Th2 secretes il-4

A

Get IgE

247
Q

What do th1 cell activate

A

Macrophages to kill organisms that they have internalized and presented

248
Q

How do cd4 T cells also influence dc during antigen presentation

A

Cd40-cd40l

249
Q

What is cd40-cd40l important for

A

Licensing DC for activation of other cells, especially naive cd8 cells

250
Q

The induction of a ctl response is dependent upon ___ T cells to provide help in the form of activation stimuli and dc licensing

A

Cd4

251
Q

Can cd8 T cells leaving the thymus lyse target cells

A

No, but they have a tcr

252
Q

What activates a pre ctl

A

Dc and cd4 T cells

253
Q

The cd4 and cd8 need to cluster in the same dc region in order for sufficient activation stimuli to be generated

A

This also ensures that the cd8 T cell is activated against a target for which there is a cd4 T cell response

254
Q

Cd4 naive T cells are only activated by dc when danger signals are present. What does this ensue

A

Ctl generation is restricted to important targets such as viruses, rather than self antigens

255
Q

What cytokines stimulate ctl

A

Il2 mainly

Also ifny

256
Q

Following activation, the CTL must prepare the machinery required to lyse target cells. What do ctl use to lyse target cells

A

Cytotoxic granule proteins
Toxic cytokines
Death inducing surface molecules

257
Q

Cytokines granule proteins are present in ____ structures proximal to the membrane

A

Lysosomal

258
Q

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

A

Polarization

259
Q

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

A

Perforin

260
Q

At the same time, ctl granules containing ____ are relapsed

A

Granzymes

261
Q

The perforin pores aid into e arrival of granzymes into the cytoplasm where they activate a cytoplasmic protein ____

A

Caspase 3

262
Q

What does active caspase 3 do

A

Cascade leads to programmed cell death also called apoptosis

263
Q

The second killing mechanism is cytokinee released directed onto the cell surface. IFNy and TNFa do what

A

Induce cell damage

264
Q

IFNy

A

Direct antiviral activity, which may be of local importance when a viral infected cell is lyse and visions released

265
Q

Tnfa

A

Toxic to a range of cell types

266
Q

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

A

Fas ligand (FasL), which binds Fas on target cells. Fas contains an intracellular death domain which leads to apoptosis via caspase activation

267
Q

What must we do with lymphocytes with an antigen receptor that could indeed by self destructive

A

Weeded out or tightly controlled

268
Q

What happens if you remove the thymus

A

Autoimmune

269
Q

What surface expression is on Treg

A

CD25 (il2 receptor a chain). Foxp3

270
Q

What do treg cells lack

A

CD127 (il7 receptor).

271
Q

Treg describe in totality

A 
CD4
CD25
CD127lo
Foxp3
CTLA4
272
Q

What do treg do

A

Cell to cell contact
Secrete il10 and tgfb
Ctla4 surface expression

273
Q

What does ctla4 do

A

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

274
Q

What percent of T cells in blood are treg

A

5-10%

275
Q

Tr1

A

Treg that produces il10

276
Q

Another subset of treg

A

Tgfb

277
Q

Bystander suppression

A

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

278
Q

Linked suppression

A

Is regulated cell is not he same apc and is responding to the same or a related antigen

279
Q

IPEX

A

Immune dysregulation, polyendocrinopathy, enteropathy, enteropathy, x linked syndrome
Defective foxp3

280
Q

For people with IPEX, what happens if you have a defective Foxp3

A

Severe inflammatory processes leafing to gut and skin disease within the first year of life
Bc of unchecked auto regulatory cells

281
Q

Most notably people with IPEX develop what

A

Type 1 diabetes

From unchecked autoreactive T cells due to the absence of thymus derived islet reactive tregs

282
Q

Are nk cells bone marrow derived lymphocytes

A

Yup

283
Q

NK cells are able to mediate their effector function ___ in the absence of previous known sensitization to that target

A

Spontaneously

284
Q

Do NK cell receptors undergo somatic recombination

A

No

285
Q

Why are NK innate immune system

A

Lack of requirement for sensitization and the absence of gene rearrangement to derive receptors for target cells

286
Q

How identify nk

A

CD16, CD56

CD3-, TCR-

287
Q

What do nk cells do

A

Kill abnormal host cells, typically cells that are virtue infected or tumor cells

288
Q

How do nk kill cells

A

Exocytosis of the lyric proteins such as perforin and granzymes and expression of FalL

289
Q

Nk secrete ifny and tnfa what does this do

A

Mediate cytotoxic effects (upregulation of MHC molecules on target cells) an activate other components of the innate (DC) and adaptive system (T cell)

290
Q

The interaction between nk and the adaptive immune system is two directional. Describe

A

Nk cell function can be influenced by b and T cells.

291
Q

Nk express cd16 and low affinity receptor for igG(FcyIIIA)

A

Nk can kill igG coated target cells in a process termed antibody dependent cellular cytotoxicity

292
Q

Nk cells use inhibitory receptors on their surface to survey targets for the presence of mhcI. If molecules are present what happens

A

Inhibition of activation

293
Q

What are the inhibitory receptors called on nk cells

A

KIRS

Killer cell immunoglobulin like receptors

294
Q

Are KIR polymorphic

A

Highly

295
Q

Ligand HLA-C

A

Receptor on nk cell

KIR2DL1

296
Q

HLA-B ligand

A

Receptor on nk cell

KIR3DL1

297
Q

ligand HLA-A molecules

A

Receptor on nk cell

KIRDL2

298
Q

HLA-E ligand molecule

A

Receptor on nk cell

NKG2A

299
Q

Ligand IgG

A

Receptor on nk cell CD16(low affinity receptor for IgG)

300
Q

ligand MHCI chain related A (MICA)

A

Receptor on nk cell

NKG2D

301
Q

HLA-C ligand

A

Receptor on nk cell

KIR2DS1

302
Q

Once contact is made, adhesion is important and is predominantly mediated by what

A

LFA1:ICAM1 interactions

303
Q

What do LFA1:ICAM1 interactions cause

A

Polarize NK cell onto its target and direct the release of granules and cytokines

304
Q

MICA

A

Receptor induced under conditions of cellular stress (infection or neoplasticism transformation)

305
Q

What is viruses can avoid CTL

A

Nk cells can kill. They sense reduced number of mhcI

306
Q

Tumors that escape immune surveillance

A

Nk cell see low MHC expression

307
Q

NK cellls are a small population of cells that resemble lymphocytes morphological but form a separate lineage from t and B cells

A

Nk cells kill tumour cells and virally infected cells without the need for prior sensitization

308
Q

Nk cells secrete cytokines (mainly ifny) which promote a cellular immune response, activating phagocytosis cells and recruiting T cells

A

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.

Immunology (14 decks)

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