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
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)
3
Q
what are the subtypes of class 1 loci?
A
HLA-A
HLA-B
HLA-C
4
Q
what are the subtypes of class 2 loci?
A
DP alpha & beta
DQ alpha & beta
DR alpha & beta
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
6
Q
describe the surface molecule of a class 2 MHC?
A
- has an alpha and beta long chain
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
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
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
10
Q
describe the inheritance pattern of MHC antigens
A
inherit 3 from mom (haplotype) and 3 from dad, expressed in co-dominant pattern
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
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.
13
Q
what class of MHC molecules do APCs present?
A
- both class 1 (CD8+) & class 2 (CD4+)
14
Q
what are some types of APCs?
A
- mononuclear phagocytes (in blood)
- macrophages (in liver/spleen/tissue)
- dendritic cells
- b-lymphocytes
15
Q
T/F Lymphocytes are phagocytic
A
False, B cells engulf via BCR, T cells just recognize MHC presented peptides
16
Q
what are skin APCs (dendritic cells) called?
A
Langerhan’s cells
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
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
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
20
Q
T/F During homeostasis, it is normal to see MHC class 1 molecules bound to peptide on the cell surface
A
True!
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
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
23
Q
what do the genes called “DOalpha & beta” encode
A
a negative regulator of DM (peptide loader/unloader)
24
Q
what are two major subsets of plasma CD4+ T-lymphocytes?
A
Th1- activate macrophages
Th2- activate B cells- grow/expand/make antibodies
25
how does the production of antibodies involve B and T cells?
- 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
26
activation of t cells require which two signals?
1. MHCII (APC) bound to TCR (t cell)
| 2. B7 (costimulatory molecule) (APC) bound to CD28 (t cell)
27
not all cells automatically have b7- how is b7 induced?
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
28
what is the immunological synapse?
- created by the sustained engagement of TCR+ MHC so that late signals (e.g. T-cell proliferation) can occur (in both CD4/CD8 cells)
29
what is in the center of an immunologic synapse?
- receptors (TCRs, CD4s, CD28s)
30
what is out the edges of an immunologic synapse?
- adhesion molecules (ICAM (APC) and LFA (t-cell))
31
what do cytotoxic T's do?
they're CD8+, recognized MHC 1 antigen presentation, directly kill cell
32
what class are helper T's ?
CD4+, class 2
33
what do HSCs in the thymus differentiate into?
Helper T's (CD4)
Cytotoxic T's (CD8)
NKTs
Tregs
34
2 diseases which prove t-cells mature in thymus
1) DeGeorge syndrome- thymus does not form, patients don't have t-cells (hypoparathyroidism)
2) FOXN1 mutation- disrupts maturation of TEC cells
35
Describe the histology of the thymus
- outer dark round cortex (developing t cells)
- inner mature medulla
- cortical-medullary junction- blood vessels, macrophages, dendritic cells
- hassall's body
36
What are the 3 cell types of the thymus gland?
1. thymic stroma- microenvironment (fibroblasts and thymic epithelial cells (TECs))
2. macrophages and dedritic cells (mature in blood)
3. lymphoid HSCs
37
What are the 4 important roles of TECs?
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
38
What is the main lympoid cell of the thymus? Which CD do they express?
thymocytes- are immature double positive cells
39
T/F You make more T-cells as you get older and battle more infections
False- t-cells decline, possibly because of adipose deposits
40
What is the timeline of t-cell differentiation?
HSC-T/NK-Pre-T-ISP-DP-CD4 OR CD8
41
Which phase is the commitment phase?
Pre-T- notch + DL1/DL4 interaction on TECs induces TCR commitment
42
What happens during the ISP phase?
immature single positive- beta selection- selection for a functional rearranged TCRBeta
pre-T= pTalpha + rearranged TCRbeta + signal transduction molecules
43
which cells undergo positive and negative selection? where does each occur?
Double positive (DP) cells
- positive= cortex
- negative= cortico-medullary region
44
describe positive selection
TCR recognizes antige + MHC on TEC
45
describe negative selection
in cortico-medullary region, high affinity cells are deleted to eliminate autoreactive cells
46
what does the AIRE gene encode?
autoimmune regulator element in TECs - induces the expression of peripheral antigens to delete t-cells that are autoreactive to organ specific antigens
47
At what stage do TCR gamma delta t-cells differentiate?
from ISP cells (before DP)
48
what is unique about gamma delta t cells? what do they recognize?
bind independent of MHC1/2; use CD1/CD2 to recognize and cytotoxically kill stressed epithelial cells
49
what do NKT cells express? what do they do?
CD4+ and CD56; are present at low levels, produce cytokines
50
what do Treg cells do? what CD factors do they have?
suppress the activity of autoreactive t-cells that escaped negative selection
- CD4, CD25
51
MHC class that recognizes CD4 (helper T's)?
MH2
52
MHC class that recognizes CD8 (cytotoxic T's)?
MH1
53
what is the evolutionary version of the alpha beta T cell and where is it found?
gamma delta t-cell, at host/environemental interfaces (respiratory system, gut, urethra, skin)
54
4 subsets of T helper cells
Th1
Th2
Th17
Treg
55
what does Th1 do?
activates macrophages, promotes cytotoxic response of CD8+ lymphocytes
56
what does Th2 do?
promotes optimal antibody production
57
what does Th17 do?
promotes chronic inflammation
58
what does Treg do?
suppresses immune response
59
what is the main example of a classic Th1 reaction? what cytokine must be dominant? what kind of reaction is induced?
TMMI, cytokine= IL-12
| - infections by organisms that require phagocytosis & need to be killed inside the cell
60
what is the transcription factor induced for Th1?
T-bet
61
what two cytokines does a mature dendritic cell up regulate? what do they do?
IL-12 & IL-18
| - initiate commitment to Th1
62
What two proteins does Th1 upregulate when it binds an antigen in the presence of the initiation cytokines?
CD-28 & CD-154 (40L)
63
What three cytokines does Th1 cell produce to propagate the TMMI response?
interferon gamma (IFNgamma), IL2, IL21
64
what does IL21 do?
promotes CD8 killing activity
65
what does IL2 do?
critical growth hormone, required for survival of Tregs, increases the expression of IL2 receptors as a functional unit
66
what does IFNgamma do?
powerful activator of macrophages, is signature cytokine of an ongoing Th1 reaction
67
where does the initiation& activation sequence of the TMMI reaction occur?
lymphoid tissue
68
what are included in the classic tetrad of pro-inflammatory cytokines
IL1
IL6
IL8
TNF alpha
69
what does IL1 do?
-prototype premordial cytokine, broad effects, produced by wide range of cell types, works with IL6, has neuroendocrine effects, facilitates responsiveness to IL2
70
what does IL6 do differently than Il1?
has strong growth & differentiation effects on B cells, involved in bone mineral (calcium) metabolism, is primary cause of fever
71
what is special about TNF-alpha?
is "the" pro-inflammatory cytokine, maintains immunologic homeostasis
72
what does IL-8 do?
mobilizes & recruits neutrophils to the site of an infection
73
what is delayed hypersensitivity?
old term for TMMI
74
describe the TMMI TB response
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
T/F NK cells have CD3 receptors
FALSE- only T cells
76
what is the signature cytokine of NK cell activation?
interferon-gamma; produce lots of it and are highly responsive to it
77
Why does a NK cell not kill RBCs?
- 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
How do NK cells kill?
- 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
what is another name for CD8 cells?
cytotoxic t-lymphocytes (CTL's)
80
CD8+ cells recognize antigen on MHC-__
MHC-1
81
what are the critical co-stimulatory signals for CD8 cells provided by and what are they?
1) NK cells- IL2 & IFN gamma
| 2) CD4 helper cells- IL21, IFN gamma, IL2
82
what is cross presentation?
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
which cytokine acts as a potent proliferative antigen to activated CD8 cells and enhances killing mechanisms?
IL-21
84
what are the two mechanisms CTLs have to kill?
1) pore formation by perforin, injection of granulozymes
| 2) apoptosis via Fas/FasL signaling
85
how do you turn off CTL cells?
- eliminate all virus so targets present nothing
| - CTLs activate own death genes, 10% remain as memory
86
what is the transcription factor induced in Th2 cells?
GATA-3
87
what is the signature cytokine produced by dendritic cells to induce a Th2 cell?
IL- 4- growth hormone of the reaction
88
what are some cells that drive the conversion of Th0 to Th2?
- ** committed Th2 cells make Il4
- B-cells presenting antigens
- dendritic cells with right TLR activated to produce IL4
- mast cells
89
what are some other cytokines that an activated Th2 can produce?
IL21- B cell stimulator
IL5, 6, 10- help B cell do isotype switch
IL4, 10, 13- suppress development of TMMI rxn
90
what is the function of the Th2 response?
enhance B cell function (growth & differentiation into plasma cells) and produce more antibodies
91
what is the transcription factor for Th17?
ROR
92
what do Th17 cells respond to? what is the signature cytokine?
- bacteria & fungi outside host cell trigger DC to produce Il-23, TGF-beta, IL6
- IL-23 is signature
93
What cytokine does Th17 produce and what does it do?
IL-17, recruits neutrophils
94
what is the transcription factor for Treg? what is another name for Treg cells?
FOXP3
| CD3,4,25+ cells
95
where do Tregs arise?
thymus and can be induced in peripheral lymphoid tissue (under the influence of regulatory cytokines like IL-10 and TGF beta)
96
what cytokine are Tregs dependent upon for survival and proliferation?
IL-2
