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SFM > T-cell Mediated Immunity > Flashcards

T-cell Mediated Immunity Flashcards

1
Q

What are the general steps of lymphocyte activation? (4)

A
  1. innate immune response to microbe (molecule induced by innate reponse (e.g. costimulator, complement fragment); this is “signal 2”
  2. microbial antigen binds to antigen receptor on lymphocyte, “signal 1”
  3. lymphocyte proliferates and differentiates
  4. adaptive immune response occurs
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2
Q

Where are naive T cell responses initiated?

A

in peripheral lymphoid organs

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3
Q

What are the effector functions activated T cells can perform?

A
  • CD4+ T cells “help” activate B cells and macrophages
  • CD8+ T cell initiate cell death of infected or transformed cells
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4
Q

What type of cell activates mature naive T cells? What type of cells activate memory T cells?

A
  • dendritic cells
  • B cells and macrophages
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5
Q

What are the general steps within DC activation? (6)

A
  1. antigen capture by DC’s which activates them
  2. lose adhesive markers (CCR1) and up regulate CCR7 expression (lymphatic endothelium)
  3. mature as they migrate (increase expression of MHC/HLA II, CD80 (B7), and LFA-1
  4. travel to regional secondary lymphoid tissue
  5. present antigen to mature, naive T cells circulating through lymph tissue
  6. secrete cytokines to promote T cell differentiation (IL-12/Th1, IL-23/Th17, IL-10/Tregs)
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6
Q

What markers would you expect to see on a mature naive cytotoxic T cell?

A

TCR/CD3 signaling complex including ζ

CD8+

MHC/HLA Class I

CD28+

LFA-1

CCR7

L-selectin

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7
Q

What markers would you expect to see on a mature naive T helper cytokine secreting cell?

A

TCR/CD3 signaling complex

CD4+

MHC/HLA Class I

CD28+

LFA-1

CCR7

L-selectin

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8
Q

What is the role of the LFA-1 receptor on lymphocytes?

A

LFA-1 is an integrin to immobilize innate immune cells through endothelial lining

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9
Q

How are T cells trafficked through the body?

A
  • Enter lymph nodes across HEV in cortex (slow down: L-selectin, CCR7; stable arrest: LFA)
  • T cells sample Ag prez by DC, if not Ag encountered, they leave through lymphatics to next node
  • T cells that encounter Ag proliferate and differentiate
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10
Q

T cell receptor: L-selectin

Ligand on endothelial cell:

Function of receptor ligand pair:

A

PNAd

Initial weak adhesion of naive T cells to HEV in lymph node

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11
Q

T cell receptor: CCR7

Ligand on endothelial cell:

Function of receptor ligand pair:

A

CCL19 or CCL21

Activation of integrins and chemokines

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12
Q

T cell receptor: LFA-1 (β2-integrin)

Ligand on endothelial cell:

Function of receptor ligand pair:

A

ICAM-1

Stable arrest on HEV in lymph node

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13
Q

What are the signal transduction receptors on CD4+ lymphocytes and their associated ligands on MHC II expressing APC’s?

A

CD4 with ligand being TCR/MHC class II complex

CD3, ITAM, ζ with no ligands on APC

CD28 with ligand of B7-1/B7-2 (CD80)

CTLA-4 with ligand of B7-1/B7-2 (CD80)

PD1 and ITIM with ligand of PD-L1/PD-L2

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14
Q

What is the first signal within T cell activation?

A

The binding of MHC/peptide complex displayed by DC to TCR on T cell

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15
Q

What happens to the receptors/ligands on T cell and DC’s during costimulation?

A
  • T cell: CD40L expression increased, CD28 constitutive
  • DC: CD40 constitutive, B7 (CD80) expression increased, cytokine secretion increased
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16
Q

During T cell activation, binding of the co-stimulatory molecules provides ______ _____ to the cell

A

second signal

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17
Q

How does TCR/HLA antigen recognition increase T cells and APC’s adhesion to one another?

A
  • TCR/HLA recognition and chemokines change integrin conformation on T cells from low affinity to high affinity
  • integrin avidity (of LFA-1 on T cell) also increases
  • this allows for clustering of adhesion molecules and firm adhesion

(LFA-1 on T cell binds to ICAM on APC)

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18
Q

Why are there 2 signals needed for T cell activation?

A
  • first signal is recognition of antigenic epitope by TCR
  • second signal maintains specificity
  • results in large number of antigen-specific effector cells from rare antigen specific naive T cell
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19
Q

What happens when T cells recognize antigen without binding of co-stimulatory ligands or cytokine support?

A

the cells will not become activated and will be unresponsive to additional stimulus: anergic or tolerant

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20
Q

What is the role of ITAM and ZAP within T cell activation?

A
  • intracellular signaling occurs through activation of immunoreceptor tyrosine-based activation motifs (ITAM)
  • kinase a/w co-receptors CD4 and CD8 phosphorylates and activates tyrosine kinase, ZAP-70, that is a/w ζ chain
  • activation of ZAP-70 on ζ chain is necessary for all downstream signaling
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21
Q

Cascade of protein prod that occurs after T cell activation:

Gene product:

  • transcription factors:

____ (minutes)

____ (hours)

  • membrane effector molecules:

_______ (hours)

_______ (hours)

  • cytokines:

____ (hours)

____ (hours to days)

____ (hours to days)

  • cytokine receptors:

_____ (hours)

A
  • transcription factors:

c-Fos (minutes)

c-Myc (hours)

  • membrane effector molecules:

CD40 ligand (hours)

Fas ligand (hours)

  • cytokines:

IL-2 (hours)

IFN-γ (hours to days)

IL-4 (hours to days)

  • cytokine receptors:

IL-2Rα (CD25) (hours)

(CD4+ express CTLA-4 and PD-1 for immune reg)

(CD8+ express PD-1 for immune reg)

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22
Q

When and why does IL-2R on T cell change?

A
  • when: after activation of T cell and secretion of IL-2 by APC
  • why: IL-2Rβγc that is constitutionally expressed on naive T cells is low affinity, it switches to IL-2Rαβγc (CD25) after activation so that IL-2 cytokine can bind with a higher affinity which promots T cell proliferation and differentiation
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23
Q

How long does it take an antigen to be bound by an antigen specific naive T cell once it has entered a lymph node?

How long does it take the effector T cells to emigrate from the lymph into periphery once activated?

A
  • 2 days (trapping of T cell)
  • 5 days (activated effector T cell emigration into periphery)
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24
Q

What is the role of CD69 in T cell activation and circulation?

A
  • when T cell is activated, it up regulates CD69 and down regulates CCR7
  • new effector T cells up regulate S1PR, however the internalization and degradation of S1PR is promoted by CD69
  • (S1PR directs T cell migration and circulation due to it binding to S1P present in blood and lymph)
  • the down regulation of S1PR leaves T cell unable to respond to migratory signals, causing temporary T cell retention in lymph nodes
  • this is to ensure activated T cell has time to provide help to other lymphocytes and ensures full activation of the T cell
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25
Q

What are the 2 main factors that drive CD4+ T helper cell differentiation?

A
  1. antigen drives the response (what microbe it is best able to combat)
  2. contributing cytokine microenvironment during activates influences differentiation
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26
Q

Th1

Cytokines:

Role:

Defense:

Pathology:

A
  • IFNγ
  • macrophage activation: pathogen lysis, prod of inflammatory mediators, phagocytosis
  • intracellular pathogens: bacteria, protozoa, viruses
  • chronic inflammation, autoimmunity
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27
Q

Th2

Cytokines:

Role:

Defense:

Pathology:

A
  • IL-4, IL-5, IL-13
  • eosinophils, mast cells, alternative macrophage activation (tissue repair), release toxic granules, mucus production
  • helminths
  • allergy
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28
Q

Th17

Cytokines:

Role:

Defense:

Pathology:

A
  • IL-17A, IL-17F
  • neutrophil activation (pathogen lysis), release of antimicrobial peptides
  • extracellular bacteria and fungi
  • autoimmunity, inflammation
29
Q

Tregs

Cytokines:

Role:

Defense:

Pathology:

A
  • IL-10, TGF-beta, CTLA-4
  • peripheral tolerance, reduce responses to harmless antigens
  • regulation of T cell responses
  • autoimmunity
30
Q

Tfh

Cytokines:

Role:

Defense:

Pathology:

A
  • IL-21, IL-4
  • support B cells in germinal center
  • extraceullar pathogens
  • antibody mediated autoimmunity?
31
Q

How do CD4+ T helper cells enhance CD8+ T cell activation?

A
  1. produce cytokines that stimulated CTL differentiation (IL-2)
  2. activate DC’s to enhance their ability to stimulate CTL differentiation by releasing cytokines (IL-12)
32
Q

What is the process of cross presentation in activation of CTL’s?

A
  • infected host cell phagocytosed by DC, which presents antigen via MHC I to CD8+ T cell and via MHC II to CD4+ helper T cells (T helper secretes IL-2 to enchance CD8+ differentiation)
  • infected DC (extremely activated) presents microbial antigen via MHC I to CD8+ T cell
33
Q
  • influenced by IL-2, IL-10, and TGF-β
  • constitutively express CTLA-4 and CD25
  • transcription factor FOXp3
  • secrete IL-10 and TGF-β
  • peripheral tolerance
A

CD4+ T regulatory cells (Treg/Th3)

34
Q
  • a type of T cell that makes up less than 5% of T cells
  • found in higher numbers at epithelial boundaries, especially gut mucosa
  • they are Ag restricted: limited diversity of peptides recognized, can recognize non-protein Ag, not restricted to MHC/HLA presentation
A

γ/δ T cells

(TCR composed of γ/δ chains instead of α/β)

35
Q

What markers would you expect to see on an effector T cell?

A

TCR/CD3 signaling complex including ζ

CD8+ (CTL), CD4+ (T helper)

MHC/HLA Class I

CD28+

FasL (CTL), CTLA-4 (T helper)

PD-1

LFA-1/VLA-4

CXCR3

E and P selectin ligand

36
Q

What is the major difference between effector T cells and resting naive, mature T cells?

A

An effector T cell is able to respond to a specific antigen without need for co-stimulation via B7 (CD80) and CD28 interaction

37
Q

How can you transfer immunity to intracellular microbes to non-immune individuals?

How are intracellular microbes killed?

A
  • by transferring “immune” T cells to non-immune individual
  • by CD8+ CTLs, activated macrophages, or NK cells
38
Q

How do effector T cells migrate to site of infection?

A
  • effector T’s enter peripheral by interacting w/ cytokines, chemokines, and adhesion molecules on endothelium at infection
  • adhesion molecules are diff for effectors than HEV’s naives interact w/:
  • slow down: E and P selectin ligand, CXCR3
  • stable arrest: LFA-1 and VLA-4
39
Q

activated/effector T cell homing receptor: E and P selectin ligand

ligand on endothelial cell:

function of receptor ligand pair:

A
  • E or P selectin
  • initial weak adhesion of effector and memory T cells to cytokine-activated endothelium at peripheral site of infection
40
Q

activated/effector T cell homing receptor: LFA-1 and VLA-4

ligand on endothelial cell:

function of receptor ligand pair:

A
  • ICAM-1 and VCAM-1
  • stable arrest on cytokine activated endothelium at peripheral site of infection
41
Q

activated/effector T cell homing receptor: CXCR3, others

ligand on endothelial cell:

function of receptor ligand pair:

A
  • CXCL10, others
  • activation of integrins and chemotaxis
42
Q

How do T helper cells migrate to site of infection?

A
  • they leave lymphatics and re-enter circulation once activated
  • they circulate until they are exposed to inflammatory molecules that allow them to migrate into peripheral tissue site of infection
43
Q

T helper 1

  • proliferate in response to ____ and ____ secreted by macrophages, NK cells, and DCs
  • unique transcription factor: ____ activated by STAT1 that is activated by IFN-γ
  • secrete: ____ and ____
  • role:
  • defense:
  • pathology:
A
  • IL-12, IFN-γ
  • T-bet
  • IFN-γ, TNF-α (also secrete IL-2 like ALL Th cells)
  • classical macrophage activation
  • intracellular pathogens
  • chronic inflammation, autoimmunity
44
Q

What does the release of IFN-γ by T helper 1 cells induce? (4)

A
  1. increases microbicidal activity by macros to intracellular microbes (classical)
  2. stimulates B cells to class switch to IgG during activation (opsonization)
  3. stimulates HLA II Ag prez and B7 (CD80) expression
  4. inhibits Th2 and Th17 production
45
Q

When a T helper 1 cell is activated, it migrates to site of infection (following chemokines) and migrates into tissue. When they encounter macros, they are presented an antigen. If the antigen fits their specific epitope, they will enhance the macros activation, how so? (3)

A
  1. macro produces ROS and increased lysosomal enzymes (increased phagolysosome killing)
  2. macro secretes cytokines (TNF, IL-1, IL-12) and chemokines (increased leukocyte recruitment)
  3. macro increases expression of B7 costimulators, MHC molecules (increased T cell response)
46
Q

T helper 2

  • proliferates in response to: ___ secreted by mast cells, basophils, and Th2 cells in immediate surroundings
  • unique transcription factor: ____
  • secretes: ___, ___, ___
  • role: _______, _____ _____, and alternative ________ activation
  • defense: ________
  • pathology: _______
A
  • IL-4
  • GATA-3
  • IL-4, IL-5, IL-13 (mucus production)
  • eosinophil, mast cell, macrophage (IgE binds to Fc portion of mast cells and promotes degranulation)
  • helminths
  • allergy
47
Q

What are the roles of T helper 2 cytokines: IL-4, IL-5, and IL-13?

(4)

A
  1. stimulate B cells to class switch to IgE (FcR for IgE on cell membranes and cross-linking of bound IgE leads to physiological responses)
  2. increased prod of mucus in epithelial cells (gut and airway, IL-13)
  3. increased eosinophil migration/activation (IL-5)
  4. alternative macrophage development
48
Q

How does T helper 2 cell provide immunity to helminths?

A
  1. mast cell activation
  2. mucus production
  3. peristalsis
  4. IgA production
  5. eosinophil activation
49
Q

What is the relationship between classically activated macrophages by Th1’s and alternatively activated macrophages by Th2’s?

A

Classically activated macros phagocytose and cause inflammation, while alternatively activated macros promote anti-inflammatory and wound repair; thus, the two macros and their functions inhibit the other

50
Q

What happens when there is a predominantly Th2 response to an intracellular microbe?

A

This leads to a poor disease outcome, as the Th2 will inhibit microbicidal activity of macrophages

51
Q

T helper 17

  • proliferates in response to ____ and ____ secreted from DC’s during activation
  • secretes: ____, ____
  • unique transcription factor: _____
  • role: ________ activation
  • defense: __________ bacteria and ______
  • pathology: __________, ________
A
  • IL-1, IL-6
  • IL-17, IL-22
  • RORγt
  • neutrophil
  • extracellular, fungi
  • autoimmunity, inflammation
52
Q
  • type of Th17 released cytokine
  • inflammatory role, recruits pro-inflammatory leukocytes, increases pro-inflammatory cyto/chemokine prod
  • stimulates anti-microbial peptide (defensins) prod
A

IL-17

53
Q
  • type of Th17 released cytokine
  • protective role, promotes regenerative responses within epithelial barrier
  • stimulates anti-microbial peptide (defensins) production
A

IL-22

54
Q

What are some general positives (3) and negatives (3) of Th17 within the immune system?

A

Positives:

  1. promotes extracellular bacteria and fungal phagocytosis by neutrophils (IL-17)
  2. important in barrier function integrity (IL-22)
  3. releases anti-microbial defensins

Negatives:

  1. has a role in inflammatory autoimmune dz: MS, IBS, RA
  2. role in integument pathology (psoriasis)
  3. role in cancers: breast/lung? (being researched)
55
Q

CD8+ CTL

  • TCR recognizes MHC/HLA I and _____ ____ peptides
  • function: killing of cells infected with _________ pathogens or ______ transformed cells by release of _____ enzymes or ____/____ induced cell death
  • ____ effector cells enchance proliferation, differentiation, and clonal expansion of activated CD8+ T cells by providing additional ____ cytokine
A
  • altered self
  • intracellular, tumor, lytic, Fas/FasL
  • Th1, IL-2
56
Q

What is unique to CD8+ CTLs regarding their binding and recognition of infected host cells or tumor altered cells?

A

CTLs do not need CD40/CD40L and CD28/B7 ligand interactions as seen in Th1 and macros. This is because CTLs need to be able to kill any infected cell in the body, not just APCs. They are tumor surveillance cells as well, thus they can respond specifically to altered self peptides via MHC I

57
Q

What are the 2 killing mechanisms of CTLs?

A
  1. cytotoxins: granules that contain lytic cytotoxins; perforin creates hole in cell wall, then the granzymes are delivered into cell via perforins and receptor mediated endocytosis, activating caspases and inducing apoptosis
  2. FasL and Fas (CD95) induction of apoptotic pathways in target host cell
58
Q

What receptors and ligands do CTLs use to bind to host cells?

A
  • CD8+ with host’s MHC I
  • LFA-1 with host’s ICAM-1
59
Q

Are CTLs able to kill more than 1 infected host cell?

A

Yes, they are serial killers. In vitro studies showed they can kill hundreds of cells qd, however in vivo studies suggested less than this due to matrix and trafficking limitations

60
Q

What is the cooperation that exists betwen T helpers and CTLs within killing of intracellular pathogens?

A

If a phagocyte ingests a microbe and presents it to T helper (via MHC II), but is not able to kill it completely and becomes infected, the CTL can come along and bind to phagocyte (via MHC I) and induce apoptosis

61
Q

NK and CTLs kill infected/tumor cells in the same manner, however they recognize altered host cells in slightly different ways. What are the slight differences in recognition and why do two recognition systems exist?

A
  • CTLs are activated by altered peptides within MHC/HLA I (viral peptide, damaged host peptide)
  • NKs are activated by decreased display of MHC/HLA I (MICA/MICB and KAR/KIR feedback)
  • the two systems are necessary because some pathogens and cancers downregulate expression of MHC/HLA I, which might elude either CTLs or NKs, thus it is good to have multiple ways to detect abnormal activity
62
Q
  • a type of humoral dependent killing of infected/damaged host cells
  • NK cell, macro, neutrophil, or eosinophil can bind to host cell via Fc portion of IgG or IgE antibodies that are bound to host cell
  • release lytic enzymes, TNF, and perforin/granzymes depending on the specific cell type
A

antibody-dependent cell-mediated cytotoxicity (ADCC)

63
Q

What happens to the T cell “clones” for a specific antigen once the infection subsides and antigenic stimulus is removed?

A

The majority of T cells undergo apoptosis, small number will become memory T cells which express increased levels of anti-apoptotic protein, Bcl-2

(this process is called contraction)

64
Q

CD4+ T regulatory cells (Tregs/Th3)

  • constitutively express _____ and _____
  • transcription factor: _____
  • ______ binds to ___ co-stimulatory ligand on APC and competitively blocks APC signaling

(binds more avidly than ____)

A
  • CTLA-4, CD25
  • FOXp3
  • CTLA-4, B7
  • CD28
65
Q

What are the two main receptors involved in contraction response of T cells?

A
  1. CTLA-4: competitive binding with B7 (CD80) on APC, binds w/ higher affinity than CD28
  2. PD-1 (also on B cells and myeloid cells), contains ITIM (immunoreceptor tyrosine-based inhibition motifs) signaling domain
66
Q

What happens when T effector cells that have started expressing regulatory ligands and are responding to chronic infections?

A

They become “exhausted” as they express increasing amounts of PD-1 and CTLA-4, yet the infection persists

67
Q
  • small population of T cells than are antigen specific
  • require reactivation to regain effector function
  • respond more rapidly than naive T cells
  • can respond in perihperal tissues
  • require IL-7 and IL-15 for survival
A

memory T cells

68
Q

Evasion mechanisms:

Mycobacteria:

HSV, CMV, EBV:

EBV:

Pox virus:

A
  • Myco: survive within phagosome
  • HSV, CMV, EBV: inhibition of antigen presentation
  • EBV: inhibition of macrophage activation
  • Pox: block cytokine activation of effector cells

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