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HST.175 Immunology > 3) T Cell Dev., Lymphocyte Homing, Activation, & Signaling, CD4 & CD8 T Cells, Memory Cells > Flashcards

3) T Cell Dev., Lymphocyte Homing, Activation, & Signaling, CD4 & CD8 T Cells, Memory Cells Flashcards

1
Q

T Cell Development: Precursors are from (X),

which then seed the (Y) (where maturation takes place)

A 
X = fetal liver and adult bone marrow
Y = thymus
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2
Q

T Cell Development: During (X) some cells can commit to γδ if they rearrange γ and δ before TCR (Y) chain rearrangement

A 
X = DN1-3
Y = β
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3
Q

T Cell Development STEP 1:

Hematopoetic Stem Cell (HSC, (X)+)

A

X = CD34

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4
Q

T Cell Development STEP 1:
(HSC) Multipotent, unrecombined TCR DNA, no TCR expression. Next Step? (X) is present (essential for T cell development) + (Y) (a cell surface molecule) is activated + (Z) (a transcription factor) is expressed = T cell lineage commitment

A 
X = IL-7 
Y = Notch-1
Z = GATA-3
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5
Q

T Cell Development STEP 2:
Double Negative Thymocyte:
At the Pro-T cell stage (X), (Y) are expressed and form Dβ-Jβ rearrangements first. As the (Z) rearrangement occurs, the cell transitions into the (A) cell stage

A 
X = DN1-3
Y = RAG1/2
Z = Vβ-DβJβ
A = Pre-T
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6
Q

T Cell Development STEP 2:
DN Thymocyte: The Pre-T cell stage (X) is entered if the rearrangement of the
TCR (Y) chain was successful (i.e. in-frame).

A 
X = DN4
Y = β
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7
Q

T Cell Development STEP 2:
DN Thymocyte, Pre-T Cell stage (DN4)
What’s on the cell-surface? The pre-TCR, which is
composed of which 4 components?

A

a. TCR β chain
b. Invariant pre-Tα
c. CD3
d. ζ proteins

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8
Q

T Cell Development STEP 2:
DN Thymocyte, Pre-T Cell stage (DN4)
What’s next? If the pre-TCR can signal, then the pre-T cell survives and proliferates, (X) chain rearrangement stops. (Y) chain rearrangement starts, (Z) expression is induced as the pre-T cell becomes a (A) thymocyte

A 
X = β
Y = α
Z = CD4 and CD8
A = double-positive
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9
Q

T Cell Development STEP 3:

DP Thymocyte: What 2 surface markers are positive?

A

CD4+, CD8+

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10
Q

T Cell Development STEP 3:

DP Thymocyte: (X) rearrangements - very early in the DP stage

A

X = Vα - Jα

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11
Q

T Cell Development STEP 3:
DP Thymocyte: If the TCRα gene is successfully rearranged, the thymocyte will have formed a complete (X) TCR. This (X) TCR has a randomly generated specificity, but only T cells with TCRs that recognize (Y) with low avidity (i.e. weakly) are stimulated to survive because of the processes of (Z)

A 
X = αβ
Y = self-MHC
Z = positive selection
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12
Q

T Cell Development STEP 3:
DP Thymocyte: In positive selection (which takes place in the (X)), the specificity of the TCR is tested via peptides bound to MHC molecules on (Y). The (Y) are presenting self (host-derived) peptides on (Z)

A 
X = thymic cortex
Y = thymic epithelial cells
Z = MHC I and MHC II
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13
Q

T Cell Development STEP 3:

DP Thymocyte: Aim 1 of Positive Selection: Delete T cells that cannot interact with self MHC (death by (X))

A

X = neglect

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14
Q

T Cell Development STEP 3:

DP Thymocyte: Aim 2 of Positive Selection: Promote the survival of cells that display (X) reactivity with self MHC

A

X = moderate

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15
Q 
T Cell Development STEP 3:
DP Thymocyte: Aim 3 of Positive Selection: Determine the class of MHC with which the TCR interacts (i.e. TCR that recognizes peptides presented on MHC II will downregulate (X) and become (Y) and one that recognizes peptides on MHC I will downregulate (Z) become (A)) and match with an appropriate surface phenotype
A 
X = CD8
Y = CD4+
Z = CD4
A = CD8+
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16
Q 
T Cell Development STEP 3:
DP Thymocyte: Positive Selection: I have taught the kinetic signaling model where all DP cells become (X). Lck binds less well to CD8. If the (X) cell sees self MHC class I moderately well, signaling is (Y) and
commitment to a CD8+ fate occurs. If the (X) cell sees MHC class II moderately well, more intense signaling occurs and a (Z) fate is obtained
A 
X = CD4+CD8low
Y = poor
Z = CD4+
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17
Q

T cells are selected to recognize (X) but go on to mature and recognize foreign (e.g. pathogen-derived) peptides in the periphery.

A

X = self-peptides

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18
Q

T Cell Development STEP 3:
DP Thymocyte:
Negative selection is the process by which T cells
whose TCR recognizes self peptide-MHC complexes (presented on (X)) with high avidity will die by apoptosis or become (Y). The thymic cortex contains only (Z = 2 cell types). The (A) contains SP thymocytes, TMECs, macrophages, DCs and pDCs.

A 
X = macrophages, dendritic cells, and medullary epithelial cells
Y = regulatory T cells
Z = TCECs and thymocytes
A = medulla
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19
Q

T Cell Development STEP 3:
DP Thymocyte: Negative selection can occur with a (X) thymocyte in the cortex with antigen being presented on (Y) thymocytes. It can also occur on a single positive thymocyte in the (Z) where antigen can be presented on (A = 4 cell types).

A 
X = double positive
Y = TCECs or DP
Z = medulla
A = DCs, Macs, pDCs and TMECs
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20
Q

When negative selection is deficient, autoimmunity occurs. For example, consider the disease called (X) (APECED) syndrome, in which there is a mutation in the
(Y) gene

A

X = autoimmune polyendocrinopathycandidiasis-
ectodermal dystrophy
Y = AIRE

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21
Q

AIRE (=autoimmune regulator) is a (X) expressed in TMECs. It induces the transcriptional expression and splicing of tissue specific antigens in the thymus. Because of AIRE, developing T cells are exposed to (Y) from the intestine, brain, liver, leukocytes, epidermis, thyroid gland, kidney,
stomach, heart, etc. while staying in the thymus!
T cells that recognize self-antigens (Z) are given signals to die. In APECED, the T cells are not negatively selected and the result is widespread organ-specific (A) via attack of
self tissues.

A 
X = transcription factor
Y = self antigens
Z = too strongly
A = autoimmunity
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22
Q

T Cell Development STEP 4:

SP Thymocyte: A thymocyte that expresses either (X) or (Y)

A 
X = CD4
Y = CD8
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23
Q

T Cell Development STEP 4:

SP Thymocyte: These T cells can finally migrate out of the (X) and into the peripheral tissues via (Y)

A 
X = thymus
Y = blood
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24
Q

What are the 3 steps in constitutive Naïve lymphocyte homing?

A

Rolling, Integrin Activation, and Sticking

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25
Q

Lymphocyte Rolling

a. Lymphocytes, granulocytes and monocytes express (X) constitutively
b. They roll on (Y) expressed on (Z) endothelium

A 
X = L-selectin
Y = PNAd
Z = HEV (High Endothelium Venule)
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26
Q

Lymphocyte Integrin activation

a. (X) on lymphocytes
b. (Y) released and bound by HEV endothelial cells

A 
X = CCR7
Y = CCL21
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27
Q

Lymphocyte Sticking

a. (X) (activated by chemokines) on lymphocytes
b. (Y) on HEV endothelium

A 
X = LFA-1
Y = ICAM
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28
Q

Lymphocyte Homing: Effector lymphocytes to inflamed tissue sites

  1. Rolling: Endothelial cells express (X) in response to “inflammation” (Y, what signals?)—not constitutively. Lymphocytes express ligands for (X) (which present sugar moieties, like (Z)) and bind (X)
  2. Still need integrin activation
  3. Sticking: (A) on lymphocytes. (B) on peripheral site endothelium
A 
X = E and P selectin
Y = IL-1, TNF, LPS
Z = sLex
A = VLA-4
B = ICAM
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29
Q

Leukocyte Homing Defects:

LAD I: (X) defect (so no sticking)

A

X = CD18 (β2 integrin)

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30
Q

Leukocyte Homing Defects:
LAD II: (X) (so no rolling, because no ligands on
HEV for (Y), and no blood group antigens)

A 
X = fucose metabolic defect
Y = L selectin
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31
Q

Leukocyte Homing Defects:

LAD III: Defect in (X) activation due to abnormal intracellular signaling

A

X = integrin

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32
Q

Leukocyte Homing Chemokines: What 2 categories can these chemokines be divided into?

A

Inflammatory (induced)

Hemostatic (constitutively expressed)

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33
Q

Chemokines are divided structurally based on the position of a pair of (X) residues: e.g. CC, CXC, CX3C, and XC

A

X = cysteine

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34
Q 
Chemokines form concentration gradients that leukocytes follow, in a
process called (X).
A

X = chemotaxis

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35
Q

(X) sense chemokines via chemokine receptors (different cell

types express unique combinations of receptors)

A

X = Leukocytes

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36
Q

Chemokine receptors
have (X) transmembrane domains and signal via (Y). There’s a complex network of interacting pairs of chemokines and chemokine
receptors (e.g. CCL3 does not interact with CCR3, but it does bind to CCR1 and CCR5)

A 
X = 7
Y = G proteins
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37
Q

Lymphocyte activation and signaling: B cell activation

What are the 2 roles for the BCR?

A

1) As a recognition molecule, which cooperates with Igα
and Igβ to send signals within the cell once antigen is bound to the BCR.
2) As an antigen internalization mechanism, taking up bound antigen,
processing it and presenting it on MHC II, thus activating Th cells leading to T cell help for the B cell

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38
Q

B cell activation: Co-receptor complex. (X)/(Y)). (X) can bind to (Z) (a degradation product of C3b) coated antigen, and synergize with BCR stimuli to activate B cells w/o T cell help and can also help phosphorylate (A) by bringing Lyn near BCR

A 
X = CD21
Y = Complement Receptor 2 or CR2
Z = C3d
A = ITAMs
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39
Q

T-independent B cell activation: If the antigen is able to both (X) the BCR and provide a second “danger” signal itself (requires repeating subunits, usually carbohydrates). The microbe can help activate (Y) and C3d can provide (Z) mediated enhanced BCR activation

A 
X = crosslink
Y = TLRs
Z = CD21
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40
Q

T-independent B cell activation: Signaling from the BCR complex ((X), NOT THE BCR ITSELF) when BCR+/- co-receptor complex binds antigen and gets (Y)

A 
X = Igα and Igβ
Y = crosslinked
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41
Q

3 steps in T-independent B cell activation:
1) First (X) (src family): i.e. Lyn phosphorylates BCRs ITAMs
2) Second (X): i.e. (Y) —binds to phosphorylated ITAMs, gets phosphorylated itself, it activates a number of cascades, via intermediates including Tec kinase (i.e.
(Z)) activation of (A) (activating calcium which activates NFκB, NFAT, etc) and other cascades.
3) Activation triggers (B) (leading to antigen presentation to T cells—T/B collaboration)

A 
X = tyrosine kinase
Y = Syk
Z = Btk
A = PLCγ
B = antigen phagocytosis
42
Q

T-dependent B cell activation (T/B collaboration): With a protein antigen, there can be both (X) by the antigen itself (signal one) as well as (Y), leading to help from (Z) cells (signal two, which leads to isotype switching and somatic
hypermutation)

A

X = BCR crosslinking
Y = antigen uptake and
presentation by MHC II
Z = helper T

43
Q

B cell activation: First T-B interaction: DC takes up protein antigen and uses (X) and pepide (plus signal 2) to activate specific (Y) cells. These T cells reduce (Z) and enhance (A) and move towards follicle. The B
cell binds antigen, endocytoses it, enhances (Z), reduces (A) and goes towards the T cell zone. The first T-B interaction at the T-B cell zone border leads to (B, 3 things) - this is an extra-follicular focus

A 
X = MHC class II
Y = CD4+ T
Z = CCR7
A = CXCR5
B = proliferation of B cells, class switching, some shortlived plasma cell formation
44
Q

B cell activation, 2nd step:
Second T-B event, activated B cells activate previously activated T cells and polarize them to (X). (X) and B cell doublets migrate into (Y)

A 
X = TFHs
Y = follicles
45
Q

What type of Helper T cells facilitates germinal center formation?

A

T follicular helper cells (TFH)

46
Q

B cell Activation: T Dependent. Germinal Centers are mostly made up of (X) which proliferate massively in the (Y) zone where they alter the affinity of their BCRs (somatic hypermutation) and then cycle to the (Z) zonewhere they interact with TFH cells and (A) which display limiting amounts of antigen and allow only the (B) antigen affinity B cells to receive TFH cell help to survive and proliferate

A 
X = B cells
Y = dark 
Z = light
A = Follicular Dendritic cells
B = highest
47
Q

B cell Activation: T Dependent: The B cells that are chosen in the GC become either (X) after they which home to the BM, and secrete antibody or (Y) which await the next infection without secreting antibody (like memory T cells—they wait for the next time the pathogen returns)

A 
X = long-lived plasma cells
Y = memory B cells
48
Q

Molecular Results of B cell activation T cell dependent antigens: Requires (X) (Helper T cell), (Y) (B cell) interaction (signaling molecules)

A 
X = CD40L
Y = CD40
49
Q

Molecular Results of B cell activation T cell dependent antigens: Somatic Hypermutation (ALTERS THE (X)). In the germinal center (Y). Mutations of the (Z) region

A 
X = DNA
Y = dark zone
Z = variable
50
Q

Somatic Hypermutation: Leads to affinity maturation of the (X) when only high affinity clones are allowed to survive the GC (based on limiting amounts of antigen presented by (Y))

A 
X = immunoglobulin
Y = follicular dendritic cells—FDCs
51
Q

Somatic Hypermutation: (X) (a cytidine deaminase in B cells) mediated i. AID: (Y) change, (Z) removes U, either get abasic site (and then replacement with any base) or (A) “fixes” w/error prone polymerase

A 
X = AID
Y = C to U
Z = UNG
A = mismatch repair
52
Q

Molecular Results of B cell activation T cell dependent antigens: Class Switch Recombination (ALTERS THE DNA). Changes the (X) (no effect on antigen specificity). Depends on switching regions 5’ of each constant region-segment. In the germinal center (Y). Leads to new effector function. Which isotype is switched to depends on
the cytokine environment (IFNγ gives IgG, IL4 gives IgE)

A 
X = Fc region/effector function
Y = dark zone
53
Q

Molecular Results of B cell activation T cell dependent antigens: Class Switch Recombination: What class of Ig cannot be switched into?

A

IgD, Cδ has no switch

region

54
Q

What ds break enzyme is Class Switch Recombination mediated by?

A

AID

55
Q

Which CDR is the most variable?

A

CDR3

56
Q

Antibodies have a constant region what what type of functions?

A

Effector

57
Q

Antibody functions: B cell receptor (BCR), the (X) bound form: recognition of antigen by the BCR and signaling by (Y) (at least) leads to proliferation and secretion of antibody

A 
X = membrane
Y = Igα and Igβ
58
Q

What isotypes of Ig activate complement?

A

secreted IgM and IgG

59
Q

What isotypes of Ig opsonize for easy phagocytosis?

A

secreted IgG, binding to phagocyte Fc receptors)

60
Q

What Isotypes of Ig are involved in cell mediated cytotoxicity?

A

Secreted IgG, IgE, IgA

61
Q

What Isotypes of Ig are involved in immediate hypersensitivity?

A

secreted IgE

62
Q

What isotypes of Ig are involved in the antibody function in Neonatal Immunity?

A

IgG2a, IgG4, IgA

63
Q

Antibodies are not the same as the membrane bound BCR form of Ig due to (X) AT RNA LEVEL

A

ALTERNATIVE SPLICING

64
Q

T Cell Activation: (X) complex is necessary

A

X = TCR

65
Q

T cell activation signaling: Co-receptors: CD4 or CD8 (bind to (X), respectively).

A

X = MHC Class II or I

66
Q

T cell activation: Signaling from the TCR (from (X), NOT TCR DIRECTLY: as heterodimers and homodimers of molecules with (Y) in their cytoplasmic tails: ε (2), δ, γ, ζ(2)) after (Z) on appropriate MHC binds to TCR)

A 
X = CD3
Y = ITAMs
Z = antigen
67
Q

What types of T cells are CD8+?

A

Cytotoxic T

lymphocytes = CTLs

68
Q

T helper cells are CD(X)+

A

X = 4

69
Q

There is significant plasticity between Th lineages
(e.g. a Th17 cell can start to produce IFN-g, and a
CD4+ T cell can express more than one of the
“master regulators”). Part of this subset stability and
plasticity is due to (X) and (Y).

A 
X = epigenetic factors
Y = MicroRNAs
70
Q

What are the 3 subtypes of Th cells?

A

Th1, Th2, Th17

71
Q

Activation of CD4+ T cells (Th) (how a naïve T cell turns into an effector T cell)
• Signal 1: Antigen presented on (X) by APC
• Signal 2 (costimulation): (Y) on T cell is stimulated by (Z)

A 
X = MHC II
Y = CD28
Z = B71/2 (both B7.1 and B7.2)
72
Q

What cytokine does Th1 produce?

A

IFN-Gamma

73
Q

What are the 2 effector functions of IFN-Gamma (Th1)?

A

1) Macrophage activation

2) Production of some antibody isotypes

74
Q

What transcription factor is necessary for Th1 cell development?

A

T-bet

75
Q

What Cytokines are necessary for Th1 cell development?

A

IFN-Gamma

IL-12

76
Q

What transcription factor is necessary for Th2 cell development?

A

GATA-3

77
Q

What 3 cytokines are produced by Th2 cells and what are their functions?

A

IL-4 (IgE production)
IL-5 (Eosinophil activation)
IL-13 (Mucosal secretions)

78
Q

What cytokine is necessary for Th2 cell development?

A

IL-4 (positive feedback)

79
Q

What transcription factor is necessary for Th17 cell development?

A

ROR-Gamma-t

80
Q

What type antigens do Th1 cells protect against?

A

Intracellular microbes

81
Q

What type antigens do Th2 cells protect against?

A

Helminthic parasites

82
Q

What type antigens do Th17 cells protect against?

A

Extracellular bacteria, fungi

83
Q

What is the role of Th1 in disease?

A

Autoimmune diseases, tissue damage associated with chronic infections

84
Q

What is the role of Th2 in disease?

A

Allergic diseases

85
Q

What is the role of Th17 in disease?

A

Organ-specific autoimmunity

86
Q

What cytokines are necessary for Th17 development?

A

IL-6, IL-1, and TGF-Beta (IL-23 and IL-21 too)

87
Q

What cytokines are produced by Th17 cells and what are their roles?

A

IL-17 (A and F) (Inflammation)

IL-22 (Barrier function)

88
Q

CD8+ T cell Activation

  1. Signal 1: Antigen presented on (X)
  2. Signal 2 ((Y)): (Z) on T cell is stimulated by (A) on APC
A 
X = MHC class I
Y = costimulation
Z = CD28
A = B7
89
Q

When the CTL recognizes an infected cell, it lyses that cell by releasing secretory granules containing (X) (to make pores in the target cell) and (Y) (enters the target cell as the membrane tries to repair the pore formed by perforin. (Y) then induces apoptosis in the target cell)

A 
X = Perforin
Y = Granzyme B
90
Q

CTLs can also kill the target cell by expressing (X), which binds to (Y) on target cell and induces apoptosis of the target cell

A 
X = FasL
Y = Fas
91
Q

What 2 cytokines do CTLs release?

A

IFN-Gamma and TNF-Alpha

92
Q

CTLs can also kill some microbes directly, via (X), which is also contained within secretory granules

A

X = granulolysin

93
Q

A T cell mediated immune response generally leads to the generation of (X) specific for that antigen, which can survive in the host for a lifetime in a quiescent state when (Y) is present.

A 
X = memory T cells
Y = IL-7
94
Q

How fast can memory cells respond compared to naive cells?

A

1-3 days vs. 5-7 days

95
Q

Memory cells are derived from (X) at several stages (e.g. they can arise before commitment to Th1/Th2, or from fully differentiated precursors)

A

X = CD4+ and CD8+ T cells

96
Q

What are the 2 general subsets of memory cells and what are their function?

A

i. Central memory T cells: home to lymph nodes because they are CCR7+ L-selectin+. When they recognize their antigen again, they very quickly generate many effector cells.
ii. Effector memory T cells: found in the periphery, e.g. mucosa. When they recognize their antigen again, they make effector
cytokines but don’t proliferate much.

97
Q

What system deals with… extracellular bacteria?

A

Th and B cells (IgG, IgM)

98
Q

What system deals with…intracellular bacteria (in phagolysosomes)?

A

TH1 yielding Macrophage activation and activated B

cells which secrete antibody to help phagocytosis by macrophages

99
Q

What system deals with…viral infections?

A

TH and CTLs (to kill the infected cells) and activated B cells (secreted antibodies can neutralize viral particles)

100
Q

What system deals with…Worms/Allergies?

A

TH2 yielding B cell activation and IgE secretion

HST.175 Immunology (4 decks)

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