Lecture 11, T Cell Immunity I Flashcards Preview

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Flashcards in Lecture 11, T Cell Immunity I Deck (53):
1

What are the 2 types of TCRs?

Alpha-beta, gamma-delta

2

What's the general definition of a naive T cell?

Mature recirculating T cells that have not yet encounter their known ag's.

3

How are T cells "activated"?

When naive T cell's TCR binds appropriate MHC/ag combo and sends a signal

4

The successful interaction of naive T cells w/ APCs results in the generation of _________ T cells.

effector

5

What surface protein do naive T cells uniquely express?

CD45RA

6

What surface protein do memory cells (derived directly from effector T cells) uniquely express?

CD45RO

7

What's the difference b/w central memory cells and effector memory cells, both of which come from effector T cells?

- Central memory: take longer than effector T cells in producing cytokines; *remain in lymphoid tissue and circulate as naïve T cells
- Effector memory: rapidly mature into effector cells upon reactivation and *enter inflamed tissues

8

*Recall: what are the 3 signals required for T cell activation? (what does each step correlate to?)

1. MHC-TCR
(Activation)
2. B7:CD28 (B7 = CD80/CD86)
(Survival)
3. Cytokines (from APC) to cytokine receptor
(Differentiation)

9

What are the "drivers" of the T cell differentiation process?

Cytokines

10

*How does an IL-2 receptor of a T cell change once the T cell is activated from naive to effector state?
- What is the CD # for this receptor?
- How does this affect the T cell?

Instead of being just gamma-delta, adds an alpha chain to receptor, increasing its affinity for IL-2. (autocrine)
(IL2r = CD25)
- Leads to T cell proliferation

11

What's the main fcn of a Cytotoxic T cell?

Kill virus-infected cells

12

What are the main fcns of a Th1 cells?

- Activate infected macrophages
- Provide help to B cells for AB production

13

What is the main fcn of a Th2 cells?

Provide help to B cells for AB production, especially switching to IgE

14

What are the 2 main fcns of a Th17 cells?

- Enhance neutrophil response
- Promote barrier integrity (skin, intestine)

15

What are the main fcns of a Thf cells (T helper follicular)?

B cell help (isotype switching, AB production)

16

What is the main fcn of a Tregs?

Suppress T cell responses
- Immune tolerance, regulation of immune response to self antigens

17

*What driver cytokines are responsible for a naive CD4+ T cell to become a Th1 cell?
What TS factor is upregulated in response?
What cytokines does the Th1 produce?

- IFN-gamma, IL-12
- Tbet
- IFN-gamma, IL-2, LT-alpha

18

*What driver cytokine is responsible for a naive CD4+ T cell to become a Th2 cell?
What TS factor is upregulated in response?
What cytokines does the Th2 produce?

- IL-4
- GATA3
- IL-4, IL-5, IL-13

19

*What driver cytokines are responsible for a naive CD4+ T cell to become a Th17 cell?
What TS factor is upregulated in response?
What cytokines does the Th17 produce?

- TGF-beta (IL-1), IL-6, IL-21, IL-23
- ROR t
- IL-17, IL-21, IL-22

20

*What driver cytokines are responsible for a naive CD4+ T cell to become a Thf cell?
What TS factor is upregulated in response?
What cytokines does the Thf produce?

- IL-6
- BCL6
- IL-6, IL-10, IL-21

21

*What driver cytokines are responsible for a naive CD4+ T cell to become a iTreg cell?
What TS factor is upregulated in response?
What cytokines does the iTreg produce?

- TGF-beta, IL-2
- FOXP3
- TGF-beta, IL-10

22

What do Th1 cells typically respond to?

Intracellular pathogens
- Important for autoimmune dz's (self)

23

What do Th2 cells typically respond to?

Extracellular pathogens
- Immunopathology of allergies, asthma, dermatitis

24

Which part of the body does Th17 help with?

Gut immunity

25

Abnormal cytokine responses are associated with serious clinical diseases can lead to ______________, which often kills patient.

Cytokine storm

26

What cells respond to "danger(ous) signals"?

DCs, macrophages

27

What do cells like DCs, macrophages, T cells, etc use to respond to intracellular viral D/RNA?

Toll-like receptors (TLRs)

28

*Where are TLRs found in/on a cell?

Membrane (sticking out, respond to parts of the pathogen), and vesicles (sticking in; respond to D/RNA).

29

What types of patterns can TLRs respond to?

- PAMPs: pathogen
- DAMPs: danger/damage
- MAMPs: microbial

30

*The recognition and uptake of a living pathogen or complex antigen by a DC triggers conversion of an “immature” DC to a mature DC.
Can the mature DC still phagocytose?
How does its MHC change?
What surface proteins does it up-regulate?
Where does it go? (via what chemokine?)
What cytokines does it up-regulate its production of?

1. No longer can phagocytose
2. Upregulates its MHC class II
3. Upregulates co-stimulatory molecules: CD80/CD86 (B7), CD40
4. Migrates to lymphoid tissue via CCR7 upregulation (chemokine receptor)
5. Upregulates production of cytokines IL-12 and IL-18

31

What part of the LN is mostly B cells?
What part of the LN is mostly T cells?

- Primary lymphoid follicle
- Paracortical area

32

What's the name of the lymphatic space that wraps around the node?
What is it called as it penetrates the cortex, moving towards the the medulla?
What is it called at the medulla?

- Marginal sinus
- Cortical sinus
- Medullary sinus

33

Where does the HEV enter the LN?

paracortical area

34

What area is b/w the paracortical area and the medullay sinus?
Most of what types of cells are there?

Medullary cords
- Macrophages, plasma cells

35

T cells enter the LN from the blood via the HEV to the paracortical area. If they do not encounter Ag that they can react to, what happens?

They leave the LN from the medullary sinus and can go onto other LNs, etc.

36

*T cells enter the LN from the blood via the HEV to the paracortical area. If they react to Ag presented by DCs, what happens to the T cell?
Can the T cell exit the LN?

They start to proliferate and *lose the ability to exit the LN. Once they differentiate into effector T cells, they can exit the LN.

37

Th1 T cells are quintessential cell type involved in what 2 general types of reactions?

- Cell mediated inflammation
- Delayed-type hypersensitivity reactions
(They are thought to be important for immunity to intracellular pathogens)

(Recall: - Activate infected macrophages
- Provide help to B cells for AB production)

38

What is the signature cytokine of the Th1 response?
What other types of cells produce this?

- IFN-gamma
- NK cells and activated CD8+ cells

39

*What are the effects of IFN-gamma?
What cells' responses it suppress (2 cell types)?

- Activate macrophages: antigen processing, MHC I and II expression, TLRs, microbicidal activity, chemokine secretion
- Potent suppressor of the Th2 and Th17 response

40

What is the general function of IL-2?
Besides Th1 cells, what other cells produce IL-2?
What type of helper T cell's growth is stimulated by IL-2?

- Growth factor
- CD8+ cells
- Tregs (also needs TGF-beta)

41

Besides Th1 cells, what other cell types produce lymphotoxin-A (LT-A)?

- CD8+ cells, NK cells, B cells, and macrophages

42

Mutation in what part of the IL-2 receptor is associated w/what dz?

HIV (and other autoimmune infections)

- When IL-2r gamma chain is mutated (delta-gamma is expressed, followed by alpha chain)

43

Although its function is not fully understood in humans, LT-A has been implicated in the development and maintenance of what? And what (2) dz pathologies is it associated with?

Lymphoid organ/environment
- RA, MS

44

*The classic tetrad of macrophage produced pro-inflammatory cytokines are:

IL-1, IL-6, IL-8 and TNF-alpha
(This is classic response to IFN-gamma)

45

What are some of the main functions of IL-1? (not sure how much we need to know)

(part of macrophage tetrad)
- Facilitates host responses to stress
- Promotes neutrophil growth and emigration from the marrow
- Acts with IL-6 on CNS to cause fever, depression
- Neuroendocrine effects on adrenal gland
- Stimulates APCs to increase Ag presentation
- Differentiation of Th17, together with TGF-β, IL6, IL21, IL23

46

What are some of the main functions of IL-6? (not sure how much we need to know)

(part of macrophage tetrad)
- Some redundant effects of IL-1 (*fever, induction of acute phase ptn CRP)
- Promotes responsiveness to IL-2, accelerates ag activation
- Required for Thf devo and optimal Th17 devo (*so IL-1 and IL-6, released by macrophages, stimulate Th17 maturation)
- Strong growth and differentiation effects on B cells in the presence of other “B” cell cytokines
- Has effects on bone mineral metabolism (activates osteoclasts)

47

What is IL-8 the most potent stimulus for?
What cells produce IL-8?

(part of macrophage tetrad)
- Most potent stimulus for mobilizing and recruiting neutrophils to the site of infection
- Produced mainly by macrophages, neutrophils, and during intense inflammation by endothelial cells

48

*What cells mediate the Hypersensitivity Reaction Type IV: Delayed-Type Hypersensitivity?
What clinical situations is this applied to? (give e.g.)

- Mediated by ag specific effector Th1 cells, CD8+ T cells
- Commonly applied to clinical situations where macrophage activation is a central component of the disease pathology. E.g. tuberculin test: DH can be exploited to detect past infections. Rxn to mosquito bites.

49

Th1 cells also stimulate monocyte production by bone marrow cells. What cytokine causes this?

IL-3/*GM-CSF

50

*After Ag is processed by tissue macrophage and stimulates Th1 cell, what is the overall response of:
1. Cytokines?
2. IFN-gamma?
3. TNF-alpna/LT?
4. IL-3/GM-CSF?
(summary)

1. Recruit macrophages
2. Express vascular adhesion molecule, activate macrophages (increase inflammatory mediators)
3. Local tissue destruction; increase in adhesion molecules
4. Stimulate monocyte production by bone marrow cells

51

What are the main functions of TNF-alpha?

*Central role in the immune system
- Potent Macrophage activator
- Potent activator of endothelial homing and adhesion molecules
- Potent upregulator of MHC and other cytokines
- Potent inducer of apoptosis and angiogenesis
- Has systemic effects that range from flu-like symptoms to death

52

Discuss the qualities of cytokines in general, aka interleukins (ILs).

- Heterodimers of two different ptns, each encoded by separate genes.
- Almost all exhibit pleiotropism and redundancy.
- Act at concentrations similar to hormones.
- Many can be produced by a wide variety of cells: immune cells, *epithelial cells.
- Lymphocytes and macrophages use cytokines to regulate the intensity of an immune response.
- Most cell/cytokine systems have agonist/antagonist (yin/yang) dynamics.
- Cytokine actions can vary and are dependent upon the state of the target cell.

53

*Cytokines orchestrate differentiation of naïve CD4 T cells into Th1 cells. These are the sequential events: (6 steps)

1. Activation of DCs/APCs by TLR ligands results in cytokine production, first IL-12 and later IL-18
2. Interaction of activated DCs/APCs with naïve CD4+ T cells: TCR with peptide MHC II, co-stimulatory molecules
3. Expression of Tbet which drive expression of IFN-gamma
4. Up-regulation of IL-12R on activated T cells which allows responding to IL-12 produced by activated DCs/APCs
5. IL-12 further induces expression of Tbet and subsequently drives the expression of signature Th1 cytokines.
6. IL-18 produced from activated DCs/APCs maintains and stabilizes Th1 response