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Host Defense > Test 1, deck 2 > Flashcards

Test 1, deck 2 Flashcards

1
Q

what is the “MHC”? How is it related to the HLA?

A
  • major histocompatibility complex
  • closely linked genetic loci (end of chromosome 6) that encode special proteins that present antigens to t-cells
  • HLA (human leukocyte antigen) is the human version of MHC
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2
Q

what cluster differentiation factors (“CD”) do the HLA classes recognize and how are they distinct?

A

Class 1 present antigens to CD8 lymphocytes (t-cells with CD8 co-receptor)- killer T’s (cytolytic)
Class 2 present antigens to CD4 lymphocytes- helper T’s (overall immune response)

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3
Q

what are the subtypes of class 1 loci?

A

HLA-A
HLA-B
HLA-C

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4
Q

what are the subtypes of class 2 loci?

A

DP alpha & beta
DQ alpha & beta
DR alpha & beta

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5
Q

describe the surface molecule of a class 1 MHC?

A
  • has one alpha chain with 3 alpha helices (2 form peptide binding site)
  • all associated non-covalently with a B2 microglobulin light chain
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6
Q

describe the surface molecule of a class 2 MHC?

A
  • has an alpha and beta long chain
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7
Q

difference is the size of peptides MHC class 1 and class 2 molecules bind?

A 
class 1- short peptides, end of the grooves are closed
class 2- longer peptides, end of grooves are opened
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8
Q

T/F the anchor residues that bind to a particular class 1 molecule do no need to be identical, but must be related (e.g. all hydrophobic)

A

True

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9
Q

When a t-cell encounters an activated macrophage, what does it recognize?

A

recognizes the bound peptide, and the 2 alpha helices forming the peptide binding cleft

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10
Q

describe the inheritance pattern of MHC antigens

A

inherit 3 from mom (haplotype) and 3 from dad, expressed in co-dominant pattern

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11
Q

what is MHC restriction?

A
  • T-cell receptor recognizes the alpha helix of 1 MHC molecule (the MHC molecule your macrophages, etc. are going to be presenting)
  • want t-cells to recognize foreign antigen presented in a specific context- dependence of t cell specific reactivity depends on foreign antigen + MHC encountered
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12
Q

which kind of cells express class 1 MHCs? class 2?

A 
class 1 MHCs- nucleated cells
class 2 MHCs- antigen presenting cells (APCs) like macrophages, neutrophils, dendritic cells, etc.
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13
Q

what class of MHC molecules do APCs present?

A
  • both class 1 (CD8+) & class 2 (CD4+)
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14
Q

what are some types of APCs?

A
  • mononuclear phagocytes (in blood)
  • macrophages (in liver/spleen/tissue)
  • dendritic cells
  • b-lymphocytes
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15
Q

T/F Lymphocytes are phagocytic

A

False, B cells engulf via BCR, T cells just recognize MHC presented peptides

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16
Q

what are skin APCs (dendritic cells) called?

A

Langerhan’s cells

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17
Q

what are the two types of dendritic cells, and why are they important?

A

1) plasmacytoid- produce interferon, protect from viruses
2) conventional- mature with encounter of antigen, present large quantities of peptide in context of MHC class II in lymphoid tissues

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18
Q

described the process by which peptides for class 1 MHC molecules are processed?

A
  • viral proteins produced in the cytoplasm
  • degraded by proteasome in cytoplasm
  • degraded proteins bind TAP1 /TAP2 for transport into the ER
  • proteins are trimmed by ERAPP in ER
  • bind class 1 MHC molecule between alpha helices
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19
Q

described the process by which class 1 MHC molecules are processed?

A
  • virus activates cell, causing the production of more MHC’s
  • MHC molecule binds calnexin to keep from misfolding in ER
  • binding of beta2microglubulin releases calnexin, calreticulin & ERp57 & tapasin bind
  • MHC molecule becomes localized right next to TAP (thanks, tapasin)
  • binds peptide
  • transported through golgi complex to cell surface
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20
Q

T/F During homeostasis, it is normal to see MHC class 1 molecules bound to peptide on the cell surface

A

True!

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21
Q

what is the difference between where class 1 and class 2 peptides come from?

A 
class 1 peptides- proteins/molecules that are from the interior of the cell
vs. 
class 2 peptides- antigens that have been endocytosed
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22
Q

described the process by which class 2 MHC molecules are processed?

A

1) invariant chain (Ii) synthesized at same time as MHII molecule, blocks peptide binding cleft in ER & initial endosome
2) Ii is dissolved by acid in endosome, CLIP is left
3) antigen endosome binds MHC endosome & is degraded, but binding site still blocked by CLIP
4) 3rd vesicle joins with HLA-DM, a peptide loader and un-loader
5) CLIP is replaced with foreign antigen, receptor travels to cell surface

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23
Q

what do the genes called “DOalpha & beta” encode

A

a negative regulator of DM (peptide loader/unloader)

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24
Q

what are two major subsets of plasma CD4+ T-lymphocytes?

A

Th1- activate macrophages

Th2- activate B cells- grow/expand/make antibodies

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25
Q

how does the production of antibodies involve B and T cells?

A
  • B cells are the APCs & make the antibodies
  • T cells produce the cytokines that allow B cells to differentiate into plasma cells (class switching) & secrete antibodies
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26
Q

activation of t cells require which two signals?

A
  1. MHCII (APC) bound to TCR (t cell)

2. B7 (costimulatory molecule) (APC) bound to CD28 (t cell)

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27
Q

not all cells automatically have b7- how is b7 induced?

A

1b. when t cells encounter matching MHCII, tcells induced to express CD40L
1c. CD40 (on APC) binds to CD40L, and induces expression of B7 by APC

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28
Q

what is the immunological synapse?

A
  • created by the sustained engagement of TCR+ MHC so that late signals (e.g. T-cell proliferation) can occur (in both CD4/CD8 cells)
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29
Q

what is in the center of an immunologic synapse?

A
  • receptors (TCRs, CD4s, CD28s)
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30
Q

what is out the edges of an immunologic synapse?

A
  • adhesion molecules (ICAM (APC) and LFA (t-cell))
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31
Q

what do cytotoxic T’s do?

A

they’re CD8+, recognized MHC 1 antigen presentation, directly kill cell

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32
Q

what class are helper T’s ?

A

CD4+, class 2

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33
Q

what do HSCs in the thymus differentiate into?

A

Helper T’s (CD4)
Cytotoxic T’s (CD8)
NKTs
Tregs

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34
Q

2 diseases which prove t-cells mature in thymus

A

1) DeGeorge syndrome- thymus does not form, patients don’t have t-cells (hypoparathyroidism)
2) FOXN1 mutation- disrupts maturation of TEC cells

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35
Q

Describe the histology of the thymus

A
  • outer dark round cortex (developing t cells)
  • inner mature medulla
  • cortical-medullary junction- blood vessels, macrophages, dendritic cells
  • hassall’s body
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36
Q

What are the 3 cell types of the thymus gland?

A
  1. thymic stroma- microenvironment (fibroblasts and thymic epithelial cells (TECs))
  2. macrophages and dedritic cells (mature in blood)
  3. lymphoid HSCs
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37
Q

What are the 4 important roles of TECs?

A
  1. produce cytokines required for growth and differentiation
  2. make ligand for Notch receptor (DL4, DL1)
  3. express MHC 1&2
  4. express tissue antigens
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38
Q

What is the main lympoid cell of the thymus? Which CD do they express?

A

thymocytes- are immature double positive cells

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39
Q

T/F You make more T-cells as you get older and battle more infections

A

False- t-cells decline, possibly because of adipose deposits

40
Q

What is the timeline of t-cell differentiation?

A

HSC-T/NK-Pre-T-ISP-DP-CD4 OR CD8

41
Q

Which phase is the commitment phase?

A

Pre-T- notch + DL1/DL4 interaction on TECs induces TCR commitment

42
Q

What happens during the ISP phase?

A

immature single positive- beta selection- selection for a functional rearranged TCRBeta
pre-T= pTalpha + rearranged TCRbeta + signal transduction molecules

43
Q

which cells undergo positive and negative selection? where does each occur?

A

Double positive (DP) cells

  • positive= cortex
  • negative= cortico-medullary region
44
Q

describe positive selection

A

TCR recognizes antige + MHC on TEC

45
Q

describe negative selection

A

in cortico-medullary region, high affinity cells are deleted to eliminate autoreactive cells

46
Q

what does the AIRE gene encode?

A

autoimmune regulator element in TECs - induces the expression of peripheral antigens to delete t-cells that are autoreactive to organ specific antigens

47
Q

At what stage do TCR gamma delta t-cells differentiate?

A

from ISP cells (before DP)

48
Q

what is unique about gamma delta t cells? what do they recognize?

A

bind independent of MHC1/2; use CD1/CD2 to recognize and cytotoxically kill stressed epithelial cells

49
Q

what do NKT cells express? what do they do?

A

CD4+ and CD56; are present at low levels, produce cytokines

50
Q

what do Treg cells do? what CD factors do they have?

A

suppress the activity of autoreactive t-cells that escaped negative selection
- CD4, CD25

51
Q

MHC class that recognizes CD4 (helper T’s)?

A

MH2

52
Q

MHC class that recognizes CD8 (cytotoxic T’s)?

A

MH1

53
Q

what is the evolutionary version of the alpha beta T cell and where is it found?

A

gamma delta t-cell, at host/environemental interfaces (respiratory system, gut, urethra, skin)

54
Q

4 subsets of T helper cells

A

Th1
Th2
Th17
Treg

55
Q

what does Th1 do?

A

activates macrophages, promotes cytotoxic response of CD8+ lymphocytes

56
Q

what does Th2 do?

A

promotes optimal antibody production

57
Q

what does Th17 do?

A

promotes chronic inflammation

58
Q

what does Treg do?

A

suppresses immune response

59
Q

what is the main example of a classic Th1 reaction? what cytokine must be dominant? what kind of reaction is induced?

A

TMMI, cytokine= IL-12

- infections by organisms that require phagocytosis & need to be killed inside the cell

60
Q

what is the transcription factor induced for Th1?

A

T-bet

61
Q

what two cytokines does a mature dendritic cell up regulate? what do they do?

A

IL-12 & IL-18

- initiate commitment to Th1

62
Q

What two proteins does Th1 upregulate when it binds an antigen in the presence of the initiation cytokines?

A

CD-28 & CD-154 (40L)

63
Q

What three cytokines does Th1 cell produce to propagate the TMMI response?

A

interferon gamma (IFNgamma), IL2, IL21

64
Q

what does IL21 do?

A

promotes CD8 killing activity

65
Q

what does IL2 do?

A

critical growth hormone, required for survival of Tregs, increases the expression of IL2 receptors as a functional unit

66
Q

what does IFNgamma do?

A

powerful activator of macrophages, is signature cytokine of an ongoing Th1 reaction

67
Q

where does the initiation& activation sequence of the TMMI reaction occur?

A

lymphoid tissue

68
Q

what are included in the classic tetrad of pro-inflammatory cytokines

A

IL1
IL6
IL8
TNF alpha

69
Q

what does IL1 do?

A

-prototype premordial cytokine, broad effects, produced by wide range of cell types, works with IL6, has neuroendocrine effects, facilitates responsiveness to IL2

70
Q

what does IL6 do differently than Il1?

A

has strong growth & differentiation effects on B cells, involved in bone mineral (calcium) metabolism, is primary cause of fever

71
Q

what is special about TNF-alpha?

A

is “the” pro-inflammatory cytokine, maintains immunologic homeostasis

72
Q

what does IL-8 do?

A

mobilizes & recruits neutrophils to the site of an infection

73
Q

what is delayed hypersensitivity?

A

old term for TMMI

74
Q

describe the TMMI TB response

A

1) macrophages/ DCs migrate to lymph nodes & present TB antigens on class II MHC to CD4 t helpers
2) T helpers are activated & migrate back to infection, encounter antigen, secrete cytokines, activate macrophages
3) now have increased population of TB reactive Th1 cells

75
Q

T/F NK cells have CD3 receptors

A

FALSE- only T cells

76
Q

what is the signature cytokine of NK cell activation?

A

interferon-gamma; produce lots of it and are highly responsive to it

77
Q

Why does a NK cell not kill RBCs?

A
  • normal, healthy cells have self-MHC which binds with KIR (killer cell inhibitory molecules)- sends signal to NK to not kill cell
  • if presenting cell has NK activating receptor as well, and the MHC is abnormal, then NK cells are activated
  • RBCs have no NK activating receptor
78
Q

How do NK cells kill?

A
  • directly, by cytotoxic mechanisms (porphorins, release granules)
    OR
  • antibody dependent cell mediated cytotoxicity (ADCC) via FC cells (recognize Fc of antibody bound to antigen, crosslinking signals NK cell to kill target cell)
79
Q

what is another name for CD8 cells?

A

cytotoxic t-lymphocytes (CTL’s)

80
Q

CD8+ cells recognize antigen on MHC-__

A

MHC-1

81
Q

what are the critical co-stimulatory signals for CD8 cells provided by and what are they?

A

1) NK cells- IL2 & IFN gamma

2) CD4 helper cells- IL21, IFN gamma, IL2

82
Q

what is cross presentation?

A

when APCs recognize viruses by TLRs, phagocytosis them, and present them on both MHC 1’s and MHC 2’s to maximize the immune response
- will eventually get killed by NK cell’s b/c of MHC I presentation

83
Q

which cytokine acts as a potent proliferative antigen to activated CD8 cells and enhances killing mechanisms?

A

IL-21

84
Q

what are the two mechanisms CTLs have to kill?

A

1) pore formation by perforin, injection of granulozymes

2) apoptosis via Fas/FasL signaling

85
Q

how do you turn off CTL cells?

A
  • eliminate all virus so targets present nothing

- CTLs activate own death genes, 10% remain as memory

86
Q

what is the transcription factor induced in Th2 cells?

A

GATA-3

87
Q

what is the signature cytokine produced by dendritic cells to induce a Th2 cell?

A

IL- 4- growth hormone of the reaction

88
Q

what are some cells that drive the conversion of Th0 to Th2?

A
  • ** committed Th2 cells make Il4
  • B-cells presenting antigens
  • dendritic cells with right TLR activated to produce IL4
  • mast cells
89
Q

what are some other cytokines that an activated Th2 can produce?

A

IL21- B cell stimulator
IL5, 6, 10- help B cell do isotype switch
IL4, 10, 13- suppress development of TMMI rxn

90
Q

what is the function of the Th2 response?

A

enhance B cell function (growth & differentiation into plasma cells) and produce more antibodies

91
Q

what is the transcription factor for Th17?

A

ROR

92
Q

what do Th17 cells respond to? what is the signature cytokine?

A
  • bacteria & fungi outside host cell trigger DC to produce Il-23, TGF-beta, IL6
  • IL-23 is signature
93
Q

What cytokine does Th17 produce and what does it do?

A

IL-17, recruits neutrophils

94
Q

what is the transcription factor for Treg? what is another name for Treg cells?

A

FOXP3

CD3,4,25+ cells

95
Q

where do Tregs arise?

A

thymus and can be induced in peripheral lymphoid tissue (under the influence of regulatory cytokines like IL-10 and TGF beta)

96
Q

what cytokine are Tregs dependent upon for survival and proliferation?

A

IL-2

Host Defense (6 decks)

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