Immunology Unit Ii

Front 1

Which class of MHC functions as part of the endogenous pathway, and which type of T cell recognizes these?

Back 1

MHC class I, recognized by CD8+ T cells

Front 2

What does it mean that a pathway of antigen processing and presentation is endogenous?

Back 2

That it takes place inside of the cytosol

Front 3

What does it mean for a pathway of antigen processing and presentation is exogenous?

Back 3

That it takes place in the "extracellular compartment," that is, in lysosomes and phagosomes and other vesicles

Front 4

Which class of MHC functions via the exogenous pathway, and which T cell type recognizes it?

Back 4

MHC class II, recognized by the CD4+ T cells

Front 5

What cellular machinery is responsible for processing the peptides in the cytosol for detection by the MHC?

Back 5

Proteasome

Front 6

Approximately how long are the proteins recognized by the cytosolic MHC, and how does this length compare to the peptides recognized by the other class?

Back 6

MHC class I molecules recognize cytosolic proteins of length ~ 8-10 aa

MHC class II molecules recognize much longer peptides of various aa lengths

Front 7

Why won't MHCs come to the surface in the absence of the recognized peptide?

Back 7

In the absence of this peptide, the molecule is unstable. The means of maintaining stability in the absence of the peptide inhibit surface expression:

-For MHC I, the protein folding isn't complete until the peptide is bound
-For MHC II, other structures in the lysosome inhibit release to the surface until peptide is loaded

Front 8

What molecular machinery transports the cytosolic peptide fragments to the ER, that they may interact with MHC I

Back 8

Transporters associated with Antigen Processing = TAP proteins

Front 9

Why are TAP proteins important?

Back 9

The MHC class I is never in contact with the cytosol. In order to bring the peptide fragments into what is essentially the extracellular space, a (ATP-dependent) pump is needed. This is the function of the TAP proteins.

Front 10

Where does peptide loading occur for MHC I?

Back 10

In the lumen of the ER

Front 11

Describe the function of the proteasome

Back 11

A part of normal homeostatic functions, the proteasome degrades cytosolic proteins that have been tagged with ubiquitin. In immune function, these proteins are responsible for producing the small 8-10aa peptides that are "seen" by MHC I

Front 12

Why must MHC and T cells come from the same strain in order to induce proliferation?

Back 12

-MHC Restriction -- positive selection in the thymus ensues T cell activation occurs only when antigen is presented by self-MHC
-MHC from different strains will bind different epitopes on the antigen peptide, and so will present differently and trigger TCRs specific for different epitopes
-Co-receptors are specific for the MHC strain of the self

Front 13

Describe the structure of the TCR

Back 13

-Resembles the Fab portion of an antibody
-Two parallel (alpha and beta) chains connected by a disulfide "hinge" between the constant regions and the transmembrane regions
-Each has a variable domain (with CDRs), a constant region, a transmembrane region, and a short cytoplasmic tail

Front 14

Define: allogenic

Back 14

Genetically different, but off the same species

Front 15

Define: syngenic

Back 15

Genetically identical

Front 16

Why is the rate of alloreactivity so high if only 1-5% of T cells are reactive to a given MHC molecule?

Back 16

Because, unless tolerance mechanisms condition anergic response, protein-dominant or MHC-dominant binding results in alloreactivity

Front 17

What is the life of a T cell after activation?

Back 17

Proliferation (clonal expansion)
Differentiation
Death

Front 18

What are the possible functions of a T cell after activation?

Back 18

-Effector T cell (either a helper T cell or a cytotoxic T cell, depending upon the co-receptor)
-Memory T cell

Front 19

Define: signal transduction

Back 19

Translation of received signals to cellular activity

Front 20

What are the proteins associated with the TCR complex?

Back 20

CD3 episilon, delta, gamma
Zeta chain
The kinases: Lck, Fyn

Front 21

What is the function of a protein kinase?

Back 21

Phosphorylation of other proteins

Front 22

How to receptor-associated protein kinases work?

Back 22

Generally inactive, these enzymes are induced by ligand binding (usually in the extracellular region) to phosphorylate other signaling molecules (on tyrosine, threonine, or serine) and thereby transmit the signal

Front 23

How does ligand binding the TCR initiate a signal?

Back 23

By causing association of the TCR complex with the co-receptor, which signals the non-covalently associated kinases to act

Front 24

What is the specificity of the SH2 domain?

Back 24

pYXXZ

That is, for phosphotyrosine (pY) and some other specific amino acid (Z) three positions away

Front 25

Define: adaptor protein

Back 25

A short (2-3 domain) protein without enzymatic function that serves to link other proteins together

Front 26

Define: scaffold protein

Back 26

A larger protein with no enymatic function that serves to recruit proteins to a signaling complex, and therefore to determine the character of a cascade

Front 27

What is the function of a second messenger, and generally what is its MO?

Back 27

Primarily to amplify a signal, but also to make it more disparate (many secondary messengers are released by single signal). Usually functions by binding some protein and thereby activating it.

Front 28

What makes PIP2 and its derivatives ideal targets for downstream perpetuation of signaling?

Back 28

Phosphoinositides are rapidly activated, but short lived -- ideal characteristics of signaling molecules.

Front 29

Define: ITAM

Back 29

The immunoreceptor tyrosine-based activation motif, present on the signaling chains of the CD3 proteins and on the zeta chains, contain tyrosine residues to be phosphorylated to become SH2 binding sites (YXXZ, Z=L,I). Typically, YXX[L/I](6-9*X)YXX[L/I]

It functions as a binding site for the kinase ZAP-70, whose two closely-spaced SH2 regions increase binding avidity.

Front 30

Define: zeta-chain

Back 30

-A disulfide-linked transmembrane homodimer whose long intracellular chains are abundant in ITAMs.
-Forms part of the TCR complex

Front 31

Define: CD3 complex

Back 31

Set of transmembrane proteins that flank the TCR. Made up of CD3(gamma), CD3(delta), and CD3(epsilon) proteins

Front 32

Through what forces is the TCR complex associated?

Back 32

Through attraction of opposite charges

Front 33

The TCR(alpha) chain is non-covalently associated with which other proteins in the TCR complex?

Back 33

-One zeta chain
-One CD3(delta):CD3(epsilon) heterodimer

Front 34

The TCR(beta) chain is non-covalently associated to which other proteins in the TCR complex?

Back 34

-One zeta chain
-One CD3(gamma):CD3(epsilon) heterodimer

Front 35

Which proteins of the TCR complex contain the ITAM, and in what concentration?

Back 35

-The CD3 proteins (delta, gamma, and epsilon) have one ITAM each
-The zeta chains have three ITAMs each

Front 36

True or False: T cell can respond to very low concentration of peptide-MHC complex on an APC surface

Back 36

True. CD4 T cells can be activated at 10-50 peptides/APC. CD8 T cells at as little as a single peptide/APC.

Front 37

What is the function and location of Lck and Fyn in TCR signaling?

Back 37

These kinases (which are structurally associated to the inner leaflet of the plasma membrane and with the co-receptor and CD3 proteins, respectively) phosphorylate the ITAMs on the TCR complex. Lck is associated with the cytoplasmic domain of the co-receptor (so activated by clumping of the co-receptor with the TCR complex), whereas Fyn is weakly associated to the zeta chains and the cytoplasmic domain of the CD3 complex proteins

Front 38

Define: ZAP-70

Back 38

This zeta-chain-associated protein contains 2 tandem SH2 domains designed to bind the ITAM. Once recruited, it is phosphorylated and activated by Lck

Front 39

If TCR:ligand binding is so weak, how are T-cell:APC complexes held together long enough for signaling?

Back 39

Proper TCR-ligand binding signals other transmembrane proteins to develop stronger interactions with transmembrane proteins on the APC, thereby establishing a "synapse"

Front 40

Which immunosuppresive drugs are most commonly prescribed for patients expecting a graft, and what functions do they target?

Back 40

Cyclosporin and FK506 block NF-AT activation

Front 41

What is the origin and function of DAG?

Back 41

The membrane-bound protein DAG, derived from cleavage of PIP2 by PLC(gamma), recruits and activates the proteins RasGRP and PKC(theta)

Front 42

What is the function of RasGRP?

Back 42

The protein RasGRP, activated by DAG, initiates the MAP kinase cascade (Raf --> Mek --> Erk --nucleus--> Erk:Elk-1), which initiates transcription of Fos, which complexes with Jun to form AP-1

Front 43

What is the function of PKC(theta)?

Back 43

PKC(theta), activated by DAG and cytosolic Ca++, initiates a cascade that leads to the degradation of I(kappa)B, de-inhibiting NF-(kappa)B, and allowing it to pass into the nucleus

Front 44

What is the origin and function of IP3?

Back 44

The cytosolic protein IP3, derived from cleavage of PIP2 by the PLC(gamma), binds channel receptors on the ER, resulting of Ca++ flow into the cytoplasm. This release activates CRACs in the plasma membrane that increase cytosolic [Ca++].

Front 45

What is the function of calmodulin?

Back 45

Calmodulin is activated by cytosolic Ca++ to bind and activated the serine phosphatase calcineurin.

Front 46

What is the function of calcineurin?

Back 46

Calcineurin, a serine/threonine phosphatase activated by the binding of calmodulin, dephosphorylates the transcription factor NFAT, allowing it to pass into the nucleus

Front 47

What is the function of ZAP-70?

Back 47

To recruit and phosphorylate the scaffold proteins SLP-76 and LAT, which subsequently are joined by the adaptor protein GADS.

Front 48

What is the function of the SLP-76-GADS-LAT complex?

Back 48

To recruit the protein PLC(gamma)

Front 49

How is PLC(gamma) activated?

Back 49

PLC(gamma), after being recruited/bound by the SLP-76-GADS-LAT complex, is activated by the kinase Itk.

Front 50

What are the known mechanisms of T cell self-tolerance?

Back 50

-Negative selection by thymic medullary epithelial cells
-Induced anergy during times of non-infection by DCs
-Treg cells

Front 51

How is self-restriction achieved in T cell development?

Back 51

By positive selection by the thymic cortical epithelial cells and ignorance-mediated death.

Front 52

What is the site of T-cell V(D)J recombination?

Back 52

The thymic cortex

Front 53

How does ignorance mediate death of T cells with too-low self-MHC affinity?

Back 53

Only cells with high-enough self MHC affinity receive survival signals from thymic cortical epithelial cells

Front 54

What condition is associated with lack of thymus in mice? In humans?

Back 54

Nude mice (because the deficiency is related to a flaw in an epithelial cell gene)
Humans with diGeorge syndrome

Front 55

Which conditions are associated with lack of V(D)J rearrangement in mice?

Back 55

The scid mouse (lacking DNA PK)
The Rag KO

Front 56

What is the function of thymic macrophages?

Back 56

To devour the cells that will not go on to become naive T cells

Front 57

Which class of MHC is most important for the selection mechanisms of the thymic epithelial cells?

Back 57

MHC II

Front 58

A cell sample from a wild-type thymus would display what ratios of dn:dp:CD4sp:CD8sp?

Back 58

dn:dp:CD4sp:CD8sp = 5:80:10:5

Front 59

What is the order of T cell development in terms of co-receptor expression?

Back 59

dn to dp to sp of either CD4 or CD8

Front 60

What are the orders of development within the dn stage in terms of expression

Back 60

CD44+CD28- --> CD44+CD28+ --> CD44-CD28+ -->CD44-CD28-

Front 61

A cell sample from a wild-type spleen would display what ratios of dn:dp:CD4sp:CD8sp?

Back 61

dn:dp:CD4sp:CD8sp = 85:0:10:5

High population of dn represents all cells that are NOT T cells

Front 62

At what phase is TCR(beta) rearranged?

Back 62

During the dn2 stage (CD4-CD8-CD44+CD28+)

Front 63

At what dn stage of T cell development do the cells, after completing TCR(beta) rearrangement, proliferate?

Back 63

During dn3 = CD4-CD8-CD44-CD28+

Front 64

What cellular event occurs during the dn2 stage?

Back 64

dn2 = CD44+CD28+ is the stage at which TCR(beta) VDJ rearrangement (D to J, then V to DJ) occurs

Front 65

What cellular event occurs during the dn3 stage?

Back 65

dn3 = CD44-CD28+ is the stage at which a productive TCR(beta) chain has been rearranged

Front 66

What cellular event occurs during the dn4 stage?

Back 66

dn4 =CD44-CD28- is the stage at which proliferation occurs and CD4 and CD8 begin to be produced

Front 67

What is the general ratio dn1:dn2:dn3:dn4 in a healthy thymus?

Back 67

dn1:dn2:dn3:dn4 = 15:5:30:50

Front 68

What does the TCR(beta):preT(alpha) complex signal?

Back 68

-Halts TCR(beta) rearrangement
-Initiates proliferation
-Signals CD4, CD8 induction
-TCR(alpha) rearrangement

Front 69

What is the name of the polypeptide that binds TCR(beta) and allows passage into the dp stage?

Back 69

preT(alpha)

Front 70

How does FACS detect the size of the cells that it sorts?

Back 70

By measuring forward scatter

Front 71

True or False: FACS plots give you information about both the number of cells in the system and the relative quantities of cells expressing different surface markers.

Back 71

False. FACS gives only relative counts, not absolute.

Front 72

What is the correlation between TCR(alpha) rearrangement and TCR:CD3 complex expression?

Back 72

Up-regulation of the entire TCR complex (as observed by noting CD3 levels) occurs after positive selection. So high expression of CD3 corresponds to a fully functional TCR(alpha+beta), whereas lower expression of CD3 corresponds to expression of the TCR(beta):preT(alpha) complex.

Front 73

True or False: A Rag KO mouse can be rescued by the addition of TCrR(beta) transgene

Back 73

True

Front 74

True or False: A RagKO/LckKO can be rescued by TCR(beta) transgene

Back 74

False

Front 75

What is the cause of the "leakage" to double positive observed in the RagKO/LckKO?

Back 75

Phosphorylation by Fyn

Front 76

True or False: The TCR(alpha) must be present before CD4/CD8 are expressed on the T cell surface

Back 76

False, CD4/CD8 expression occurs at the same time as VJ(alpha) rearrangement is initiated

Front 77

At what stage of development and in what compartment of the thymus do "selective events" begin?

Back 77

At the dp stage in the cortex of the thymus

Front 78

What is the dn:dp:spCD4:spCD8 for MHCI/MHCII KO?

Back 78

dn:dp:spCD4:spCD8 = 5:95:0:0 for MHCI/MHCII KO

Front 79

What type of cell migrates from the bone marrow to the thymus to develop into a T cell?

Back 79

T cell progenitor

Front 80

What is the name given to the prospective T cells developing in the thymus?

Back 80

Thymocytes

Front 81

What are the selection mechanisms/functions that occur in the thymus?

Back 81

Positive selection
Neglect-induced thymocyte death
Negative selection

Front 82

Ultimately, about what percent of thymocytes survive to be naive T cells?

Back 82

2%

Front 83

Describe the process of positive selection

Back 83

After forming a proper TCR, the dp thymocyte is tested for ability to recognize MHC on thymic cortical epithelial cells. Cells that can recognize this marker are given the signal to survive

Front 84

Describe the process of negative selection

Back 84

Cells that survive positive selection interact with dendritic cells and medullary epithelial cells. Cells that are found to be too reactive are killed.

Front 85

What subset of cells become the Tregs?

Back 85

The narrow subset of cells that are more reactive than ordinary CD4/CD8 T cells, but not so reactive that they are killed, experience down-regulation of CD8 andup-regulation of CD25, and become Tregs

Front 86

What function of the thymus results in MHC restriction

Back 86

Positive selection

Front 87

What interaction results in promotion of the thymocyte to the sp stage?

Back 87

MHC recognition at the corticomedullary junction

Front 88

True or false: Irradiation kills all immune-system-related cells, including thymic epithelial cells

Back 88

False: All cells of the hematopoeic system are killed, but thymic epithelial cells are preserved.

Front 89

What is the purpose of irradiating the mouse when making a radiation chimera?

Back 89

To kill the cells of the hematopoeic system

Front 90

What are the steps to making a radiation chimera, and what's the point?

Back 90

To make a mouse whose T cells recognize a different MHC from that presented by the APCs by having bone marrow and thymic epithelial cells come from different strains.

Irradiate mouse of strain A, rest for 2 hrs., inject bone marrow cells from mouse of strain B.

Front 91

If T cell progenitors come from strain B, but thymus comes from strain A, to what strain of MHC will the mouse be restricted?

Back 91

Strain A MHC

Front 92

The MHC expressed in which cells dictates MHC restriction?

Back 92

The thymic cortical epithelial cells

Front 93

Roughly what percentage of TCRs are rescued by positive selection?

Back 93

10-30%

Front 94

What is the typical lifespan of an ignored dp cell?

Back 94

3-4 days

Front 95

What function results in the limited appearance of CD4+ T cells in MHC class II thymus transgenic mice?

Back 95

Endogenous VJ alpha chain rearrangement

Front 96

Which thymic process regulates the development of the thymocyte into EITHER CD4 or CD8?

Back 96

Positive selection

Front 97

Activated CD4 T effector cells have what effector function?

Back 97

As helper T cells, they release cytokines to help modulate appropriate immune response to the specific infection type

Front 98

Activated CD8 T effector cells have what effector function?

Back 98

Cytotoxic T cells kill infected body cells

Front 99

What transcription factor is associated with Treg development?

Back 99

FoxP3

Front 100

At what stage of development (in terms of co-receptor expression) does negative selection occur?

Back 100

Throughout thymocyte development, but in our simplified schema, after positive selection somewhere in the dp-sp range as cells reach the corticomedullary junction (where they begin to interact with DCs and medullary epithelial cells)

Front 101

What is the function of the transcription factor AIRE?

Back 101

To express and present in the thymus important self-peptides that would not ordinarily be produced in the thymus

Front 102

What is APECED and what is its cause?

Back 102

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy is a deficiency in the TF AIRE, leading to the release of naive T cells that are sensitive to tissue-specific self peptides.

Front 103

Define: avidity

Back 103

The strength of binding calculated as the product of binding sit affinity by number of binding sites

Front 104

Describe the pathway of T cells between leaving the thymus and being activated

Back 104

T cells enter the bloodstrream through venuoles in the thymic medulla, where they circulate until they reach secondary lymphoid organs by either

-Collecting at the spleen, or
-Entering the T cell zone of lymph nodes through high endothelial venuoles (HEVs)

where they'll encounter (and be activated by) APCs. If not activated, they return to the circulation via the efferent lymphatic vessel and thoracic duct.

Front 105

What is the function of the secondary lymphoid organs?

Back 105

To bring together immune cells

Front 106

What are the three major APCs?

Back 106

B cells, macrophages, and DCs

Front 107

Why don't B cells make good T cell activators?

Back 107

B cells are "selfish" and tend to present antigen for activated (CD4 effector) T cells to activate them

Front 108

What makes dendritic cells good activators of T cells?

Back 108

-They express both classes of MHC
-They express costimulatory peptides (B7, for signal 2)
-They express TLRs sensitive to PAMPs (for signal 3)
-The are present in the tissues, and move effectively to lymph nodes after activation
-As immature DCs (in tissues) they're highly endocytic and express high numbers of TCRs
-As mature DCs (in secondary lymphoid organs), they're not very endocytic, and express high concentration of MHC and co-stimulatory ligands

Front 109

How do APCs enter the lymph nodes?

Back 109

Through the afferent lymphatic vessel

Front 110

What T cell ligand do B7 molecules bind, and to what effect?

Back 110

B7 molecules on APCs bind T cell surface proteins CD28 to initiate signals that stabilize IL-2 mRNA and activates AP-1 and NF(kappa)B, with a total net 100-fold increase in IL-2 secretion

Front 111

TCR-signaling-induced [Ca++] leads to upregulation of which transcription factor(s)?

Back 111

-NFAT most directly
-Through activation of PKC(theta), also increases NF(kappa)B

Front 112

Describe the process of TCR signaling

Back 112

Binding of MHC complex by TCR stabilized by co-receptor binding. Co-receptor binding increases proximity of Lck, which (with Fyn) phosphorylates ITAMs on zeta-chain and CD3 complexes. Activated ITAMs recruit Zap-70 (via SH2 binding of ITAMs), which activates scaffold proteins LAT and SLP-76, bound through GADS. This structure binds PLC(gamma), which cleaves PIP2 into DAG and IP3. IP3 increases intracellular [Ca++], which stimulates calmodulin to activate calcineurin, which activates the transcription factor NFAT. DAG initiates two pathways:

-Through PKC(theta), it signals dephosphorylation/activation of NF(kappa)B
-Through RasGRP it initiates the MAP kinase cascade (Raf -- Mek -- Erk) to activate Erk to pass into the nucleus and dimerize with Jun to produce the transcription factor AP-1

Front 113

What is the transcription factor product of RasGRP?

Back 113

AP-1

Front 114

What pathways does DAG activate?

Back 114

-Transcription of AP-1 through the RasGRP
-Transcription NF(kappa)B through PKC(theta)

Front 115

What is the transription factor product of PKC(theta) signaling?

Back 115

NF(kappa)B

Front 116

What is the function of IL-2?

Back 116

Autocrine T cell activation signal

Front 117

Why is B7 costimulation necessary?

Back 117

Inactivation of self reactive cells that make it past negative selection mechanisms in the thymus

Front 118

Define: peripheral tolerance

Back 118

Tolerance achieved by causing anergy in T cells that receive signal 1 (TCR:MHC) without signal 2 (CD28:MHC) to ensure inactivation of self-reactive T cells that escape negative selection at the thymus.

Front 119

What experimental method is most useful for exploring tolerance mechanisms?

Back 119

Selecting for autoimmunity in double transgenic mice. (e.g. Anti-HA tg TCRs + expression of HA @ pancreatic beta cells)

Front 120

Define: central tolerance

Back 120

Tolerance achieved by negative selection by thymic medullary epithelial cells and dendritic cells in the thymic medulla to ubiquitous self peptides and (via AIRE) to certain cell peptides produced in specific tissues

Front 121

What mechanism of action is generally associated with Tregs?

Back 121

Maintenance of tolerance by suppressing T cell proliferation in absence of co-stimulatory cytokines secreted by DCs

Front 122

Define: dominance peripheral tolerance

Back 122

Tolerance by Treg suppression of T cell proliferation in absence of (DC-secreted) cytokines signaling infection

Front 123

By what immunological research technique is cytokine-secretion studied/quantified?

Back 123

By ELISA

Front 124

Define: MyD88

Under what circumstances would it be advantageous to knock it out?

Back 124

MyD88 is an adaptor protein in the pathway of signaling initiated by TLRs.

MyD88 knockout would be valuable in an experiment in which one wanted to knock out TLR function.

Front 125

What is the importance of TLR signaling to DC function?

Back 125

TLR signaling enables activation of DC for presentation of MHC and of B7 of for production of cytokines that determine pathway of Th cell differentiation.

Front 126

Describe the mechanism of Th cell activation of B cell

Back 126

B cell signal 1 = antigen binding to BCR. Internalization and expression of antigen:MHC complex

Th cell signal 1 = TCR:MHC complex forms with B cell MHC:antigen complex

Th cell signal 2 = CD28:B7 complex

B cell signal 2 = (T cell)CD40L:(B cell)CD40 + T cell cytokine secretion

Results in proliferation, differentiation (incl. class-switch) B cell

Front 127

Where does T cell-mediated B cell activation occur?

Back 127

In the B cell zone of the lymph node (T cells migrate there after activation)

Front 128

True of false: B cells express TLRs

Back 128

True: TLR signaling in B cells is essential for up-regulation of MHC and B7, which is necessary for T cell-mediated B cell activation

Front 129

Will a vaccine work in the absence of innate immune stimulation? Why or why not?

Back 129

No. Without immune stimulation, DCs will not upregulate B7, such that any recognized MHC:antigen complex will result in anergy, rather than acquired immunity

Front 130

What are the differences in activation between naive and effector T cell activation mechanisms?

Back 130

Naive T cells require 2-3 signals, whereas effector T cells can be activated by a single signal

Front 131

What are the known types of Th cells?

Back 131

Th1, Th2, Th17

Front 132

Th cells descend from which type of naive T cell?

Back 132

CD4 T cells

Front 133

What is the approximate size of a cytokine?

Back 133

Small. Less than 30 kDa.

Front 134

What is the general function of a cytokine?

Back 134

Intercellular signaling (may be autocrine, paracrine, or endocrine), by binding membrane-bound receptors on a target cell with the ultimate result of up-regulating expression of a gene

Front 135

Give an example of cytokines for each type of signaling (autocrine, paracrine, endocrine)

Back 135

Autocrine: IL-2, IL-4
Paracrine: IFN(gamma), Type I IFN
Endocrine: IL-5 (which acts on bone marrow)

Front 136

What is the general signal transduction pathway for cytokines?

Back 136

-Cytokine binds a receptor, causing dimerization.
-Dimerization activates associated JAK (=Janus kinase)-family tyrosine kinases to phosphorylate STAT-family proteins
-STATs contains SH2 motifs, causing dimerization upon phosphorylation
-Dimeric STAT may pass into the nucleus and act as a transcription factor

Front 137

A naive CD4 T cell activated in the presence of IL-12 and IFN(gamma) will develop into what kind of effector cell?

Back 137

A Th1 effector cell, which produces IFN(gamma)

Front 138

A naive CD4 T cell exposed to IL-4 at activation will develop into what kind of effector cell?

Back 138

A Th2 effector cell, which produces IL-4, IL-5, and IL-13

Front 139

A naive CD4 T cell exposed to IL-23 at activation will develop into what kind of effector cell?

Back 139

A Th17 cell, which produces IL-17 and IL-21

Front 140

What is the function of a Th1 cell?

Back 140

To respond to intracellular bacterial or viral attack by producing IFN(gamma), induce B cell class switch to IgG2 (to induce opsonization), activate macrophages, and aid in CTL differentiation

Front 141

What cytokine(s) induce differentiation to Th1?

Back 141

IL-12, IFN(gamma)

Front 142

Describe the feedback mechanisms that occur when a CD4 T cell is activated in the presence of a cytokine that dictates a specific lineage of Th

Back 142

The same factors that promote development into one form of Th will antagonize the other pathways

Front 143

What is the function of a Th2 cell?

Back 143

To defend against attack by a worm or large parasite by upregulation of IL-4, IL-5 and IL-13, inducing B cell class-switch to IgE, and encouraging differentiation and activation of eosinophils

Front 144

Which cytokines induce development of naive CD4 T cell into a Th2 cell?

Back 144

IL-4

Front 145

Which cytokine(s) induce(s) development of naive CD-4 T cell into a Th17 cell?

Back 145

IL-23

Front 146

What is the function of Th17 cells?

Back 146

To defend against extracellular bacteria by producing IL-17, IL-21 and inducing recruitment of neutrophils by chemokine-secretion at somatic (epithelial) cells

Front 147

Where is Th17 function most important?

Back 147

At mucosal surfaces

Front 148

What is the primary function of IgG antibodies?

Back 148

Neutralization (in some cases, complement activation and opsonization, too)

Front 149

What is the main function of IgE antibodies?

Back 149

To induce degranulation of eosinophils and mast cells to create harsher environments for extracellular bacteria

Front 150

How does the DC know to secrete which cytokine in response to an infection?

Back 150

In the case of Th1, TLR signaling guides release of appropriate cytokine. Mechanisms for Th2, Th17 are yet unknown.

Front 151

What experiments work well to analyze function CD8 T cells?

Back 151

CD8 T cells function by cell-mediated cell lysis, so a measurement of lysis of targeted cells would determine the effectiveness of CD8 cell action. This is achieved through the 51Cr-release assay, by which target cells are incubated with a radioactive chromium compound, then mixed with different concentrations of CD8 T cell. % lysis is measured by appearance of 51Cr (which is taken up spontaneously, but not released) and compared to non-specific effector T cell.

Front 152

What experiments work well to analyze T cell activation?

Back 152

T cell activation can be studied by determining whether proliferation will occur at a second activation. Proliferation (by mitosis) requires replication of DNA, which requires dNTs. The taking-up of radiolabeled thymidine is telling of the amount of proliferation that has occured.

Front 153

What does IL-17 do, and where does it come from in response to infection?

Back 153

IL-17, which is produced by Th17 cells, acts on somatic cells in the case of extracellular or fungal infection to release antimicrobial peptides and chemokines that recruit neutrophils to the site of infection

Front 154

What is the master-regulator of T cell development to become a Treg?

Back 154

FoxP3

Front 155

What is the master-regulator of T cell development to become a Th1 cell?

Back 155

Tbet

Front 156

What is the master-regulator of T cell development to become a Th2 cell?

Back 156

Gata3

Front 157

What is the master-regulator of T cell development to become a Th17 cell?

Back 157

ROR(gamma)t

Front 158

What is the danger of the negative feedback mechanisms in the Th cell development pathway?

Back 158

Cytokine bias can lead to improper responses and therefore increased sensitivity to certain diseases (i.e. leishmania in mice or leprosy in humans)

Front 159

The tuberculoid form of leprosy corresponds to which Th response, and what degree of virulence?

Back 159

The tuberculoid form of leprosy refers to the (appropriate) Th1 response.

Front 160

The lepromatous form of leprosy corresponds to which Th response, and what degree of virulence?

Back 160

The lepormatous form corresponds to the (inappropriate) Th2 response.

Front 161

What is the function of Fas?

Back 161

Fas protein in the thymus is responsible for inducing apoptosis in negatively selected T cells in the thymus.

Front 162

Which IL-2 transcription factors are up-regulated in response to the second signal?

Back 162

NF(kappa)B and AP-1