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PHARM 321 > Lecture 17 Cell-mediated Immunity > Flashcards

Lecture 17 Cell-mediated Immunity Flashcards

1
Q

Describe a TCR.

A

2 polypeptide chains disulphide linked
a chain
B chain
1 V and C domain each and transmembrane region.
V region unique and created by gene rearrangement.
Antigen binding site formed by 3 CDR/HV loops of each chain at amino terminus
Resembled the FAB portion of an Ig
Single binding site for Ag vs two per Ig.

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2
Q

Describe the TRC gene loci and recombination.

A

a/B chains are fragmented in gremlin config.

a-chr14
similar to Ig light chain
only V+J
Single Ca section

B-chr7
similar to Ig heavy chain locus
VDJ recombination
two indistinguishable CB sections

Recombination involves RAG complex to produce functional gene and TCR with high mono specificity.

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3
Q

What is different between B and T cells after antigen stimulation?

A

After antigen stimulation, B cells undergo affinity maturation, somatic hypermutation, isotype switching etc.
Antigen stimulation does not induce changes in the gene as with B cells
Thus TCR have more of a role in recognition of Ag and not mediating effector functions.

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4
Q

Describe TCR assembly? Which proteins are involved?

A

TCR a / B assembled in the ER but cannot leave without accessory proteins.
a/B associate with 4 transmembrane proteins termed the CD3 complex:
gamma, delta, epsilon, Zeta.
CD3 functions in TCR signalling.
CD3 association allows transport of the TCR to the cell surface.

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5
Q

What is the alternate version of TCR?

A

the gamma/delta T cells:
do not contain the a/B chains
Cells will only express a/B or y/d
y/d more common in tissues than in circulation, more similar to NK cells
y/D receptor recognition is not dependent on MHC
d-chain locus is found within the a-chain. DNA rearrangement often deletes this segment.
less variation than a/B
increased junctional diversity

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6
Q

What does antigen processing and presentation have to do with TCR?

A

TCR can only recon Ag in the form of a short 8-25 aa peptide bound to an MHC molecule.
So, pathogen-derived proteins must first be degraded into peptides and complexed with an MHC
Ag processing destroys 3D structure unlike in Ig.
Many Ag polypeptides can be generated from an Ag

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7
Q

What are the main types of effector / activated T cells?

A

CD4 helper T cells
Trigger other immune cells to respond to infection
Th1: activates macrophage
Th2: activates b-cells, aby production

CD8 cytotoxic T cells
Directly kill virally infected host cells

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8
Q

What are the T cell coreceptors?

A

CD4 and CD8

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9
Q

Describe the physical properties of the CD4 and CD8 coreceptors.

A

CD4: single pp with 4 extracellular Ig-like domains

CD8: Heterodimer: 1 a and 1 B each having a single extracellular Ig-like domain

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10
Q

Describe the two MHC variants.

A

MHC1: expressed on all nucleated cells, surveys cytoplasm for infection.
Isotypes: A,B,C,E,F,G
3 domain transmembrane alpha subunit.
Associated B2 microglobulin

MHC2: expressed on APCs. Surveys extracellularly for pathogens, internalized, broken down, presented.
Macrophages, B cells, Dendritic cells
Isotypes: DM, DO, DP, DQ, DR
a and B transmembrane peptides each with two Ig domains.

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11
Q

Describe the players necessary for binding between MHC and TCR.

A

MHC1-Ag-TCR
CD8 coreceptor

MHC2:Ag:TCR
CD4 coreceptor

The co-receptors stabilize MHC-ag-presentation. They bind to the domains of MHC not forming the antigen binding site.

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12
Q

Describe the binding specificity of MHC.

A

Degenerate: They can bind a range of peptides whereas Ig and TCR only bind a very specified 1-few.

MHC1 binds 8-10aa as 2 ends of pp are bound in grooves at end.

MHC2 bind larger pp like 13-25+ as there are not pockets at end like in MHC1

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13
Q

Describe the production of peptide presenting MHC class I and II.

A

Class 1:
Intracellular antigen is processed into peptides by proteasome.
TAP transports these antigenic peptides into the ER where Tapacin presents them so they can bind with MHC class 1.
the MHC 1:Ag is sent through the golgi / vesicles to the cell surface for presentation to CD8 T cells

Class 2:
An extracellular antigen is endocytosed, phagocytksed. MHC2 from the ER is blocked from binding peptides by Invariant chain / CLIP.
MHC2 travels in vesicle which merges with a phagolysosome. CLIP is dislodged by HLA-DM and peptides present in phagolysosome can bind. MHC 2:ag sent to cell surface for presentation.

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14
Q

What is peptide editing?

A

Tapacin interacts with MHC 1 so that the binding pocket is in a more open configuration. Only peptides binding with a high tightness will bind and dislodge tapacin. Other proteins are involved in shortening peptides that are too long to bind to the MHC1 groove.

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15
Q

How is MHC diversity created?

A 
Diversity is provided by:
different gene families,
genetic polymorphism,
meiotic recomination,
point mutations.
MHC ag binidng diversity is genetically determined and varies from one person to the next like a shuffling of cards. We all have different haplotypes.
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16
Q

What are the different human MHC isotypes and which are most polymorphic?

A

HLA: Class 1: a,b,c most polymorphic e,g less polymorphic, f least polymorphic B-2 micro globulin is monomorphic.
Class 2: DP,DQ,DR most polymorphic then DM and DO

17
Q

What is MHC restriction?

A

TCR recognizes specific mix of Ag and MHC isotype. Changing the Ag or isotype of MHC will result likely in non binding and non recognition.

18
Q

What are the leukocyte adhesion molecules?

A 
Leukocyte Selectins (lectins)
Vascular addressins (mucin like)
Leukocyte Integrin receptors
ICAMS
CD2: Lymphocyte Function associated Ag (LFA)
19
Q

Detail T cell homing to lymphoid tissue.

A

Circulating lymphocyte enters endothelial venue in lymph node.
Leukocyte selectins bind vascular addressing weakly promoting a rolling interaction. Leukocyte integrins bind vascular ICAMS promoting tight binding.
Diapedesis occurs where the lymphocyte leaves the blood and enters the lymph node.
Chemokines promote tight binding interaction.

Selection - lectin
Addressin - glyCAM and cd34
integrin LFA1

20
Q

Detail the journey of an antigen from a site of infection to a lymph node via an APC.

A

At a site of infection, dendritic cells take up antigens and pathogens (which they break down into antigens) and present them. Dendritic cells leave the site of infection through a lymph vessel and enter via an afferent lymph vessel into a draining lymph node. Once the dendritic cell makes it to the T cell area in the lymph node, it differentiates into a mature dendritic cell (up regulation of MHC and B7) that specializes in activating naive T cells.

21
Q

What are examples of APCs and what are some of their characteristics / functions?

A

Dendritic cells, macrophages, B cells

Meet / reside in secondary lymphoid tissues.
Have MHC II + I; process and present antigens to T cells.
Express co-stiulatory B7 (ligand for t cell CD28) during an infection.
Expression of MHC and B7 upregulated during an infection.

22
Q

How do macrophages present the presence of an external infection to T cells?

A

Macrophages take up and break down pathogens by phagocytosis. Peptides are presented on MHCII.

The presence of an infection induces an up regulation of MHC and co-stimulatory ligand B7.

Binding of a matching T cell TCR and co-receptor to ag:MHC and T cell CD28 to macrophage B7 induces proliferation and differentiation of T cells.

23
Q

What is the role of IL-2 in antigen presentation to T cells?

A

Binding of MHC and B7 signals for the T cell to express the a chain of the IL-2 receptor as well as IL-2. The a chain along with the B and y chains already present in the membrane produce a high affinity IL-2 receptor. The IL-2 that the T cell produces binds to its IL-2 receptor to sustain activation and undergo proliferation.

24
Q

What is T cell Anergy?

A

If there is an MHC:Ag:TCR signal but no co-stimulatory B7:CD28 signal, the cell becomes anergic or non-responsive to further signals. This happens when an APC has presented a self peptide but since there is no infection, no costimulatory B7 is present. Anergy and self-tolerance results rendering T cells that might become self-reactive that have escaped negative selection inert.

25
Q

What functions can CD4 T cells acquire after activation?

A

Naive CD4 T cells can become Th1 cells (macrophage activation) or Th2 cells (B cell / aby stimulation). The functions of these cells may change with the local cytokine environment that the activated T cell exists in.

26
Q

What functions can CD8 T cells acquire after activation?

A

Naive CD8 T cells are activated by dendritic cells and Th cells to cytotoxic effector cells.

Il-2 activation by autocrine, co-stimulatory, or paracrine method is important.

Cytotoxic effector cells induce apoptosis in virally infected self-cells.

27
Q

What is the autocrine method of CD8 T cell activation?

A

A virally infected cell produces ag-MHC1 and B7. The T cell binds with TCR, CD8, CD28. Internal IL2 production and self-stimulation results in proliferation and differentiation of CD8 T cells.
In this case, the signals from the infected cell are sufficient to induce activation.

28
Q

What is the co-stimulatory method of CD8 T cell activation?

A

In this case, the signal from an APC is insufficient to activate the CD8 cell.
The APC needs a boost from an effector CD4 cell.

Naive CD8 TCR binds MHC1.
Effector CD4 TCR binds MHC2.
The combo of binding induces an up regulation of B7 in the APC.
Both T cells now bind B7 through CD28.
The CD8 T cell now has a sufficient signal to upregulae IL2 receptor alpha and Il2.
Il2-further stimulates and results in proliferation and differentiation of the CD8 cell.

29
Q

What is the paracrine method of CD8 T cell activation?

A

In this case, the APC activates a bound CD4 T cell which produces IL-2 that stimulates a bound CD8 T cell to differentiate.

30
Q

How does an effector (cytotoxic) CD8 T cell mediate apoptosis?

A 
The cytotoxic cell surveys cells for presence of a matching MHC-Ag. Initial collision and non-specific adhesion by cell adhesion molecules does not immediately result in release of lytic granules.
Specific recognition of the TCR to its matching MHC:ag results in firm adhesion and reorganization of the ER and granules towards the infected cell. 
Lytic granules (perforin, granulysin, serglycin) are released at the site of cell contact which crease pores to deliver apoptotic (cell disrupting) proteins (granzymes) into the infected cell. Fas ligand binds the Fas receptor on the infected cell to induce apoptosis.
31
Q

What are some properties of apoptotic vs necrotic cells?

A

Apoptotic cells have distinct compartments, there is chromatin condensation and vesicle shedding but a well defined pm.
Necrotic cells do not have defined cell organization nor condensed DNA.

32
Q

What are the effector molecules of cytotoxic T cells?

A 
perforin
granzymes
Fas ligand
IFN-y
TNFa/B
33
Q

What are the effector mlcs or Th1 cells?

A 
IFN-y
GM-CSF
TNF-a
CD40 ligand
Fas ligand
IL-3
TNF-B
IL-2
34
Q

What are the effector mlcs or Th2 cells?

A 
IL-4, 5, 15
CD40
IL-3
GM-CSF
IL-10
TGF-B
eotaxin

PHARM 321 (11 decks)

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